Compounds that inhibit mcl-1 protein

ABSTRACT

Provided herein are myeloid cell leukemia 1 protein (Mcl-1) inhibitors, methods of their preparation, related pharmaceutical compositions, and methods of using the same. For example, provided herein are compounds of Formula I, 
     
       
         
         
             
             
         
       
     
     or a stereoisomer thereof; and pharmaceutically acceptable salts thereof and pharmaceutical compositions containing the compounds. The compounds and compositions provided herein may be used, for example, in the treatment of diseases or conditions, such as cancer.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 62/479,171, filed on Mar. 30, 2017, and U.S. Provisional Application No. 62/479,230, filed on Mar. 30, 2017, both of which are hereby incorporated by reference in their entireties and for all purposes as if fully set forth herein.

FIELD OF THE INVENTION

The present invention relates to compounds that inhibit myeloid cell leukemia 1 protein (Mcl-1, also abbreviated as MCl-1, MCL-1 or MCL1); methods of treating diseases or conditions, such as cancer, using the compounds; and pharmaceutical compositions containing the compounds.

BACKGROUND OF THE INVENTION

One common characteristic of human cancer is overexpression of Mcl-1. Mcl-1 overexpression prevents cancer cells from undergoing programmed cell death (apoptosis), allowing the cells to survive despite widespread genetic damage.

Mcl-1 is a member of the Bcl-2 family of proteins. The Bcl-2 family includes pro-apoptotic members (such as BAX and BAK) which, upon activation, form a homo-oligomer in the outer mitochondrial membrane that leads to pore formation and the escape of mitochondrial contents, a step in triggering apoptosis. Antiapoptotic members of the Bcl-2 family (such as Bcl-2, Bcl-XL, and Mcl-1) block the activity of BAX and BAK. Other proteins (such as BID, BIM, BIK, and BAD) exhibit additional regulatory functions.

Research has shown that Mcl-1 inhibitors can be useful for the treatment of cancers. MCl-1 is overexpressed in numerous cancers. See Beroukhim et al. (2010) Nature 463, 899-90. Cancer cells containing amplifications surrounding the Mcl-1 and Bcl-2-1-1 anti-apoptotic genes depend on the expression of these genes for survival. Beroukhim et al. Mcl-1 is a relevant target for the re-iniation of apoptosis in numerous cancer cells. See G. Lessene, P. Czabotar and P. Colman, Nat. Rev. Drug. Discov., 2008, 7, 989-1000; C. Akgul Cell. Mol. Life Sci. Vol. 66, 2009; and Arthur M. Mandelin II, Richard M. Pope, Expert Opin. Ther. Targets (2007) 11(3):363-373.

New compositions and methods for preparing and formulating Mcl-1 inhibitors would be useful.

SUMMARY OF THE INVENTION

In one aspect, the present invention comprises a compound of Formula I:

a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, wherein:

Z is C or N;

Q is O, S, CR^(WA)R^(WB), or NR^(a)R^(b);

W is CR^(WA)R^(WB), —C═O, or is absent;

R^(WA) and R^(WB) are independently selected from H, —C₁₋₃alkyl, —C₂₋₃alkenyl, —C₂₋₃alkynyl, halo, —OH, or —O—C₁₋₃alkyl;

b, represented by the symbol

is a single or double chemical bond which may be cis or trans;

R¹ is independently selected from H, halo, C₁₋₆alkylhalo, C₁₋₆alkyl, C₂₋₆alkenyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), or —C(═O)NR^(a)R^(b); R² is selected from H, halo, C₁₋₆haloalkyl, C₁₋₆alkyl, O—C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkenylene, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), —C(═O)NR^(a)R^(b), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl or heterocycloalkyl group have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O or SO₂;

R³ is selected from H, —C₁₋₆alkylhalo, —C₁₋₆alkyl, —C₂₋₆alkenyl, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a), —C(═O)OR^(a), or —C(═O)NR^(a)R^(b);

each of R^(2B), R^(2C), R⁴, R⁵, R⁶, R⁷, and R⁸ is independently selected from H, halo, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), —C(═O)NR^(a)R^(b), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

alternatively R³ and R⁴ together with the atoms to which they are bonded may form a 5- to 12-membered ring, optionally containing a heteroatom selected from a N, O or S atom, in addition to the S and N atoms present in the ring, wherein the ring may optionally contain at least one double bond; and the ring may be substituted with 0, 1, 2, or 3 R^(3A) substituents;

wherein R^(3A) is selected from H, halo, —OH, C₁₋₆haloalkyl, C₁₋₆alkyl, O—C₁₋₆alkyl, C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), or —C(═O)NR^(a)R^(b);

each of R^(4A), R^(5A), R^(6A), R^(7A), and R^(8A) is independently selected from H, OH, halo, or —C₁₋₆alkyl;

R^(7A) and R^(8A) are absent when b is a double chemical bond;

alternatively R⁷ and R⁸ together with the atoms to which they are bonded may form a 3- to 12-membered ring, wherein the ring may optionally contain at least one double bond;

R⁹ is independently selected from H, OH, -(═O), —C₁₋₆haloalkyl, —C₁₋₆alkyl, —C₁₋₆alkenylene, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —C₁₋₆alkyl-O—C₁₋₆alkyl, cyano, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl or heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl group may include a C═O group, and further wherein the spiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O or SO₂;

R^(9A) is independently selected from H, —OH, halo, cyano, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁₋₆alkenylene, —(CH₂CH₂O)_(n)R^(a), —P(═O)OR^(a)OR^(b), —CSR^(a), —CS(═O)R^(a), —SR^(a), —SOR^(a), —OSO₂R^(a), —SO₂R^(a), —(CH₂CH₂O)_(n)CH₃, -(═O), —C(═O), —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —CH₂—NR^(a)R^(b), —NR^(a)R^(b), —C₁₋₆alkyl-O—C₁₋₆alkyl, —OC₁₋₆alkyl, —O—C₁₋₆alkyl-O—C₁₋₆alkyl, phenyl, a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may contain a double bond and may contain a C═O group, and further wherein the spiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O or SO₂;

wherein R^(9A) is not H when W is absent;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of the R^(9A) substituent can be unsubstituted or substituted with 1, 2, 3 or 4 R¹⁰ substituents independently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆alkynyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 0, 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

alternatively R⁷ and R^(9A) together with the atoms to which they are bonded may form a 3- to 12-membered ring, wherein the ring may optionally contain at least one double bond;

alternatively R⁹ and R^(9A) together with Q, W, and the C to which W and Q are bonded, may form a 3- to 12-membered monocyclic or bicyclic ring, optionally containing a heteroatom in addition to Q that is selected from N, O or S, wherein the ring may contain a double bond, wherein the ring may optionally include a C═O group, and further wherein the ring optionally may be substituted by 1, 2, or 3 R¹¹ substituents;

R¹¹ is independently selected from H, —OH, halo, —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —NR^(c)R^(d), —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(c), —C(═O)OR^(c), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl group may include a double bond, and wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl group may include a C═O group, and further wherein the spiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O or SO₂;

wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and the —OC₁₋₆alkyl of any of the R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R^(4A), R^(5A), R^(6A), R^(7A), R^(8A), R^(9A), R^(WA) and R^(WB) substituents is unsubstituted or substituted by 1, 2 or 3 R¹² substituents independently selected from OH, —OC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, halo, —O-haloC₁₋₆alkyl, —CN, —NR^(a)R^(b), —(NR^(a)R^(b)R^(c))_(n), —OSO₂R^(a), —SO₂R^(a), —(CH₂CH₂O)_(n)CH₃, -(═O), —C(═O), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —O—SiR^(a)R^(b)R^(c), —SiR^(a)R^(b)R^(c), —O-(3- to 10-membered heterocycloakyl), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O or SO₂;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl group of any of the R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9A), R¹⁰, R¹¹, R¹², R^(WA) and R^(WB) substituents can be unsubstituted or substituted with 1, 2, 3 or 4 R¹³ substituents independently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups of R¹³ have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, and spiroheterocycloalkyl groups of R¹³ or the heterocycloalkyl group of R¹³ may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

wherein each R^(a), R^(b), R^(c), and R^(d) is independently hydrogen, OH, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₁₋₆alkyl-NR¹⁴R¹⁴, —NR¹⁴R¹⁴, —SO₂R¹⁴, —(CH₂CH₂O)_(n)CH₃, -(═O), —C(═O)R¹⁴, —OC(═O)R¹⁴, —C(═O)OR¹⁴, —C(═O)NR¹⁴R¹⁴, —C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, benzyl, phenyl, —C₁₋₆alkyl-C(═O)OH, —C₁₋₆alkyl-C(═O)—O—C₁₋₆alkyl, —C₁₋₆alkyl-cycloalkyl, —C₁₋₆alkyl-heterocycloalkyl, —C₁₋₆alkyl-6- to 10-membered aryl, —C₁₋₆alkyl-6- to 10-membered heteroaryl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, where the heteroaryl, spiroheterocycloalkyl, heterocycloalkyl group or the —C₁₋₆alkyl-heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, heterocycloalkyl, group of R^(a), R^(b), R^(c), and R^(d) or the heterocycloalkyl group or the —C₁₋₆alkyl-heterocycloalkyl group may include a double bond and may contain a C═O group, and the spiroheterocycloalkyl, or heterocycloalkyl may include a S═O or SO₂;

the alkyl, aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, or heterocycloalkyl group of R^(a), R^(b), R^(c), and R^(d) and the heterocycloalkyl group of the —C₁₋₆alkyl-heterocycloalkyl group of R^(a), R^(b), R^(c), and R^(d) can be unsubstituted or substituted with 1, 2, 3, or 4 R¹⁴ substituents, wherein each R¹⁴ is independently selected from H, —OH, —N═N═N, halo, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, phenyl, tolyl, —C(═O)C₁₋₆alkyl, —C(═O)O—C₁₋₆alkyl, N(CH₃)₂ or —SO₂—N(CH₃)₂; and

wherein n is independently in each instance an integer of 1, 2, 3 or 4.

In another aspect, the present invention comprises a compound of Formula I′:

a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, wherein:

Z is C or N;

Q is O or S;

W is CR^(WA)R^(WB) or C═O;

R^(WA) and R^(WB) are independently selected from H, C₁₋₃alkyl, halo, —OH, or —O—C₁₋₃alkyl;

b, represented by the symbol

is a single or double chemical bond which may be cis or trans;

R¹ is independently selected from H, halo, C₁₋₆alkylhalo, C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), or —C(═O)NR^(a)R^(b);

R² is selected from H, halo, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), or —C(═O)NR^(a)R^(b),

R³ is independently selected from H, —C₁₋₆alkylhalo, —C₁₋₆alkyl, —C₂₋₆ alkenyl, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a), —C(═O)OR^(a), or —C(═O)NR^(a)R^(b);

each of R⁴, R⁵, R⁶, R⁷, and R⁸ is independently selected from H, halo, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), —C(═O)NR^(a)R^(b), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

alternatively R³ and R⁴ together with the atoms to which they are bonded may form a 5- to 12-membered ring, optionally containing a heteroatom selected from a N, O or S atom, in addition to the S and N atoms present in the ring, wherein the ring may optionally contain at least one double bond; and the ring may be substituted with 0, 1, 2, or 3 R^(3A) substituents;

R^(3A) is independently selected from H, halo, —OH, C₁₋₆haloalkyl, C₁₋₆alkyl, O—C₁₋₆alkyl, C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), —C(═O)NR^(a)R^(b);

each of R^(4A), R^(5A), R^(6A), R^(7A), and R^(8A) is independently selected from H, OH, halo, —C₁₋₆alkyl;

R^(7A) and R^(8A) are absent when b is a double chemical bond;

R⁹ is independently selected from H, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

R^(9A) is independently selected from H, C₁₋₆haloalkyl, C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b), —N═N═N, —C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of the R^(9A) substituent can be unsubstituted or substituted with 1, 2, 3 or 4 R¹⁰ substituents independently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆alkynyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 0, 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

alternatively R⁹ and R^(9A) together with Q, W, and the C to which W and Q are bonded, may form a 3- to 12-membered monocyclic or bicyclic ring, optionally containing a heteroatom in addition to Q that is selected from N, O or S, wherein the ring may contain a double bond, wherein the ring may optionally include a C═O group, and further wherein the ring optionally may be substituted by 1, 2, or 3 R¹¹ substituents;

R¹¹ is independently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl or heteroaryl, a 6- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl group have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

wherein the —C₁₋₆alkyl of any of the R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R^(4A), R^(5A), R^(6A), R^(7A), R^(8A), and R^(9A) substituents is unsubstituted or substituted by 1, 2 or 3 R¹² substituents independently selected from OH, —OC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, halo, —O-haloC₁₋₆alkyl, —CN, —NR^(a)R^(b), —(NR^(a)R^(b)R^(c))_(n), —SO₂R^(a), —(CH₂CH₂O)_(n)CH₃, (═O), —C(═O), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —O—SiR^(a)R^(b)R^(c), —O-(3- to 12-membered heterocycloakyl), phenyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of any of the R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² substituents can be unsubstituted or substituted with 1, 2, 3 or 4 R¹³ substituents independently selected from OH, halo, —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —NR^(c)R^(d), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), —B(OH)₂, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

wherein each R^(a), R^(b), R^(c), and R^(d) is independently H, OH, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₂₋₆alkynyl, —C₁₋₆alkyl-NR¹⁴R¹⁴, NR¹⁴R¹⁴, —SO₂R¹⁴, —(CH₂CH₂O)_(n)CH₃, (═O), —C(═O)R¹⁴, —OC(═O)R¹⁴, —C(═O)OR¹⁴, —C(═O)NR¹⁴R¹⁴, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-OH, benzyl, phenyl, a —C₁₋₆alkyl-3- to 12-membered heterocycloalkyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups and r the heterocycloalkyl group of the —C₁₋₆alkyl-heterocycloalkyl group have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, heterocycloalkyl, and the heterocycloalkyl groups of the —C₁₋₆alkyl-heterocycloalkyl group may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

the alkyl, aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, heterocycloalkyl and the heterocycloalkyl groups of the —C₁₋₆alkyl-heterocycloalkyl groups of R^(a), R^(b), R^(c), and R^(d) can be unsubstituted or substituted with 1, 2, 3, or 4 R¹⁴ substituents independently selected from H, OH, —N═N═N, halo, —C₁₋₆alkyl, —OC₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, phenyl, tolyl, —C(O)C₁₋₆alkyl, —C(O)OCH₃, SO₂-phenyl, or —SO₂—N(CH₃)₂; and

n is independently, in each instance, an integer of 1, 2, 3 or 4.

In another aspect, the compound of Formula I′ has Formula II′a:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof.

Another aspect of the present invention provides a pharmaceutical composition that includes the compound of any of the embodiments or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

Another aspect of the present invention provides a method of treating cancer. Such methods include: administering to a patient in need thereof a therapeutically effective amount of the compound of any of the embodiments or a pharmaceutically acceptable salt thereof. In some such methods, the cancer is a hematologic malignancy. In some such methods, the cancer is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia, and acute myelogenous leukemia. In some other such methods, the cancer is multiple myeloma. In some other such methods, the cancer is acute myelogenous leukemia. In some other such methods, the cancer is non-Hodgkin's lymphoma. In another aspect, the method further includes administering to a patient in need thereof a therapeutically effective amount of an additional pharmaceutically active compound. For example, in some such methods the additional pharmaceutically active compound is carfilzomib. In others, the additional pharmaceutically active compound is venetoclax. In still other such methods, the additional pharmaceutically active compound is cytarabine.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

Other features and advantages of the disclosure will be apparent from the following detailed description and figures, and from the Claims.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 demonstrates the superior in vivo efficacy of Example 1 relative to Reference Compound 1 in a tumor PD model. Both compounds were dosed orally to female athymic nude mice inoculated with OPM-2 Luc cells.

FIG. 2 demonstrates the superior in vivo efficacy of Example 2 and Example 3 relative to Reference Compound 1 in a tumor PD model. Both compounds were dosed orally to female athymic nude mice inoculated with OPM-2 Luc cells.

FIG. 3 demonstrates the superior in vivo efficacy of Example 4 relative to Reference Compound 1 in a tumor PD model. Both compounds were dosed orally to female athymic nude mice inoculated with OPM-2 Luc cells.

FIG. 4 demonstrates the superior in vivo efficacy of Example 10 relative to Reference Compound 1 in a tumor PD model. Both compounds were dosed orally to female athymic nude mice inoculated with OPM-2 Luc cells.

FIG. 5 demonstrates the superior in vivo efficacy of Example 11 relative to Reference Compound 1 in a tumor PD model. Both compounds were dosed orally to female athymic nude mice inoculated with OPM-2 Luc cells.

FIG. 6 demonstrates the superior in vivo efficacy of Example 13 and Example 14 relative to Reference Compound 1 in a tumor PD model. Both compounds were dosed orally to female athymic nude mice inoculated with OPM-2 Luc cells.

FIG. 7 demonstrates the superior in vivo efficacy of Example 18 relative to Reference Compound 1 in a tumor PD model. Both compounds were dosed orally to female athymic nude mice inoculated with OPM-2 Luc cells.

FIG. 8 demonstrates in vivo efficacy of Example 1 in an OPM-2 xenograft efficacy model. Example 1 was dosed orally to female athymic nude mice inoculated with OPM-2 Luc cells.

FIG. 9 demonstrates in vivo efficacy of Example 4 in an OPM-2 xenograft efficacy model. Example 1 was dosed orally to female athymic nude mice inoculated with OPM-2 Luc cells.

FIG. 10 demonstrates in vivo efficacy of Example 10 in an OPM-2 xenograft efficacy model. Example 1 was dosed orally to female athymic nude mice inoculated with OPM-2 Luc cells.

FIG. 11 demonstrates in vivo efficacy of Example 11 in an OPM-2 xenograft efficacy model. Example 1 was dosed orally to female athymic nude mice inoculated with OPM-2 Luc cells.

FIG. 12 demonstrates in vivo efficacy of Example 13 in an OPM-2 xenograft efficacy model. Example 1 was dosed orally to female athymic nude mice inoculated with OPM-2 Luc cells.

FIG. 13 demonstrates in vivo efficacy of Example 18 in an OPM-2 xenograft efficacy model. Example 1 was dosed orally to female athymic nude mice inoculated with OPM-2 Luc cells.

DETAILED DESCRIPTION

The symbol “—” represents a covalent bond and can also be used in a radical group to indicate the point of attachment to another group. In chemical structures, the symbol — is commonly used to represent a methyl group in a molecule.

As used herein, chemical structures which contain one or more stereocenters depicted with dashed and bold bonds (i.e.,

and

) are meant to indicate absolute stereochemistry of the stereocenter(s) present in the chemical structure. As used herein, bonds symbolized by a simple line do not indicate a stereo-preference. Unless otherwise indicated to the contrary, chemical structures that include one or more stereocenters which are illustrated herein without indicating absolute or relative stereochemistry encompass all possible stereoisomeric forms of the compound (e.g., diastereomers, enantiomers) and mixtures thereof. Structures with a single bold or dashed line, and at least one additional simple line, encompass a single enantiomeric series of all possible diastereomers.

As used herein, the term “about” is meant to account for variations due to experimental error. All measurements reported herein are understood to be modified by the term “about,” whether or not the term is explicitly used, unless explicitly stated otherwise. As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

The term “alkyl” means a straight or branched chain hydrocarbon. Representative examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl and hexyl. Typical alkyl groups are alkyl groups having from 1 to 8 carbon atoms, which groups are commonly represented as C₁₋₈ alkyl.

The term “compound”, as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates).

The term “cycloalkyl” means a cyclic, nonaromatic hydrocarbon. Representative examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A cycloalkyl group can contain one or more double bonds. Representative examples of cycloalkyl groups that contain double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl and cyclobutadienyl. Common cycloalkyl groups are C₃₋₈ cycloalkyl groups.

The term “excipient”, as used herein, means any pharmaceutically acceptable additive, carrier, diluent, adjuvant or other ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and/or administration to a patient. Handbook of Pharmaceutical Excipients, 5^(th) Edition, R. C. Rowe, P. J. Sheskey, and S. C. Owen, editors, Pharmaceutical Press, 2005, Hardback, 928, 0853696187.

For the terms “for example” and “such as” and grammatical equivalences thereof, the phrase “and without limitation” is understood to follow unless explicitly stated otherwise.

The term “halogen” or “halo” means F, Cl, Br or I.

The term “patient” means subjects including animals, such as dogs, cats, cows, horses, sheep and humans. Particular patients are mammals. The term patient includes males and females.

The term “patient in need” means a patient having, or at risk of having, one or more diseases or conditions where the Mcl-1 protein is involved, such as cancers. Identifying a patient in need can be in the judgment of a subject or a health care professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).

The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection, and infusion.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

The term “pharmaceutically acceptable” is employed herein to refer to those ligands, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for administration to a patient, commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. As used herein the language “pharmaceutically acceptable carrier” includes buffer, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch, potato starch, and substituted or unsubstituted β-cyclodextrin; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain Claims, pharmaceutical compositions provided herein are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient.

The term “pharmaceutically acceptable salt” refers to the relatively non-toxic, inorganic and organic acid addition salts of a compound provided herein. These salts can be prepared in situ during the final isolation and purification of a compound provided herein, or by separately reacting the compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulphonate salts, and amino acid salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66: 1-19). The phrases “systemic administration”, “administered systemically”, “peripheral administration”, and “administered peripherally” as used herein mean the administration of a ligand, drug, or other material via route other than directly into the central nervous system, such that it enters the patient's system and thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

The term “therapeutically effective amount” means an amount of a compound that ameliorates, attenuates or eliminates one or more symptom of a particular disease or condition, or prevents or delays the onset of one of more symptom of a particular disease or condition. The terms “treating”, “treat” or “treatment” and the like include preventative (e.g., prophylactic) and palliative treatment.

Embodiments A

The embodiments listed below are presented in numbered form for convenience and for ease and clarity of reference in referring back to multiple embodiments.

In a first embodiment, the present invention comprises a compound of Formula I′:

a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, wherein:

Z is C or N;

Q is O or S;

W is CR^(WA)R^(WB) or C═O;

R^(WA) and R^(WB) are independently selected from H, C₁₋₃alkyl, halo, —OH, or —O—C₁₋₃alkyl;

b, represented by the symbol

is a single or double chemical bond which may be cis or trans;

R¹ is independently selected from H, halo, C₁₋₆alkylhalo, C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), or —C(═O)NR^(a)R^(b);

R² is selected from H, halo, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), or —C(═O)NR^(a)R^(b),

R³ is independently selected from H, —C₁₋₆alkylhalo, —C₁₋₆alkyl, —C₂₋₆ alkenyl, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a), —C(═O)OR^(a), or —C(═O)NR^(a)R^(b);

each of R⁴, R⁵, R⁶, R⁷, and R⁸ is independently selected from H, halo, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), —C(═O)NR^(a)R^(b), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

alternatively R³ and R⁴ together with the atoms to which they are bonded may form a 5- to 12-membered ring, optionally containing a heteroatom selected from a N, O or S atom, in addition to the S and N atoms present in the ring, wherein the ring may optionally contain at least one double bond; and the ring may be substituted with 0, 1, 2, or 3 R^(3A) substituents;

R^(3A) is independently selected from H, halo, —OH, C₁₋₆haloalkyl, C₁₋₆alkyl, O—C₁₋₆alkyl, C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), —C(═O)NR^(a)R^(b);

each of R^(4A), R^(5A), R^(6A), R^(7A), and R^(8A) is independently selected from H, OH, halo, —C₁₋₆alkyl;

R^(7A) and R^(8A) are absent when b is a double chemical bond;

R⁹ is independently selected from H, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

R^(9A) is independently selected from H, C₁₋₆haloalkyl, C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b), —N═N═N, —C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of the R^(9A) substituent can be unsubstituted or substituted with 1, 2, 3 or 4 R¹⁰ substituents independently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆alkynyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 0, 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

alternatively R⁹ and R^(9A) together with Q, W, and the C to which W and Q are bonded, may form a 3- to 12-membered monocyclic or bicyclic ring, optionally containing a heteroatom in addition to Q that is selected from N, O or S, wherein the ring may contain a double bond, wherein the ring may optionally include a C═O group, and further wherein the ring optionally may be substituted by 1, 2, or 3 R¹¹ substituents;

R¹¹ is independently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl or heteroaryl, a 6- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl group have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

wherein the —C₁₋₆alkyl of any of the R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R^(4A), R^(5A), R^(6A), R^(7A), R^(8A), and R^(9A) substituents is unsubstituted or substituted by 1, 2 or 3 R¹² substituents independently selected from OH, —OC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, halo, —O-haloC₁₋₆alkyl, —CN, —NR^(a)R^(b), —(NR^(a)R^(b)R^(c))_(n), —SO₂R^(a), —(CH₂CH₂O)_(n)CH₃, (═O), —C(═O), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —O—SiR^(a)R^(b)R^(c), —O-(3- to 12-membered heterocycloakyl), phenyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of any of the R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² substituents can be unsubstituted or substituted with 1, 2, 3 or 4 R¹³ substituents independently selected from OH, halo, —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —NR^(c)R^(d), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), —B(OH)₂, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

wherein each R^(a), R^(b), R^(c), and R^(d) is independently H, OH, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₂₋₆alkynyl, —C₁₋₆alkyl-NR¹⁴R¹⁴, NR¹⁴R¹⁴, —SO₂R¹⁴, —(CH₂CH₂O)_(n)CH₃, (═O), —C(═O)R¹⁴, —OC(═O)R¹⁴, —C(═O)OR¹⁴, —C(═O)NR¹⁴R¹⁴, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-OH, benzyl, phenyl, a —C₁₋₆alkyl-3- to 12-membered heterocycloalkyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups and r the heterocycloalkyl group of the —C₁₋₆alkyl-heterocycloalkyl group have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, heterocycloalkyl, and the heterocycloalkyl groups of the —C₁₋₆alkyl-heterocycloalkyl group may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

the alkyl, aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, heterocycloalkyl and the heterocycloalkyl groups of the —C₁₋₆alkyl-heterocycloalkyl groups of R^(a), R^(b), R^(c), and R^(d) can be unsubstituted or substituted with 1, 2, 3, or 4 R¹⁴ substituents independently selected from H, OH, —N═N═N, halo, —C₁₋₆alkyl, —OC₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, phenyl, tolyl, —C(O)C₁₋₆alkyl, —C(O)OCH₃, SO₂-phenyl, or —SO₂—N(CH₃)₂; and

n is independently, in each instance, an integer of 1, 2, 3 or 4.

2. Another embodiment of the present invention comprises the compound of Embodiment 1, wherein the compound of Formula I′ has the Formula I′a:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof.

3. The compound of any one of Embodiments 1 or 2, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein b is a double bond.

4. The compound of any one of Embodiments 1 or 2, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein b is a single bond.

5. The compound of any one of Embodiments 1-4, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein Z is C.

6. The compound of any one of Embodiments 1-4, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein Z is N.

7. The compound of any one of Embodiments 1-6, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein Q is O.

8. The compound of any one of Embodiments 1-6, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein Q is S.

9. The compound of any one of Embodiments 1-8, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein W is C═O.

10. The compound of any one of Embodiments 1-8, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein W is CR^(WA)R^(WB.)

11. The compound of any one of Embodiments 1-8 and 10, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(WA) and R^(WB) are both H.

12. The compound of any one of Embodiments 1-11, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹ is halo.

13. The compound of any one of Embodiments 1-12, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹ is Cl.

14. The compound of any one of Embodiments 1-13, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R² is H.

15. The compound of any one of Embodiments 1-14, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R³ is H or —C₁₋₆ alkyl.

16. The compound of any one of Embodiments 1-15, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R³ is —CH₃.

17. The compound of any one of Embodiments 1-15, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R³ is H.

18. The compound of any one of Embodiments 1-17, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is independently selected from H, —C₁₋₆alkyl, —C₁₋₆alkylhalo, —C₁₋₆alkyl-O—C₁₋₆alkyl, or —(CH₂CH₂O)_(n)R^(a), wherein the —C₁₋₆alkyl is unsubstituted or substituted with —OH, (═O), phenyl, —O—SiR^(a)R^(b)R^(c), —NR^(a)R^(b), a 3- to 12-membered cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from O, N or S.

19. The compound of any one of Embodiments 1-18, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is H.

20. The compound of any one of Embodiments 1-18, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —C₁₋₆alkyl.

21 The compound of any one of Embodiments 1-18 or 20, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —CH₃.

22. The compound of any one of Embodiments 1-18, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —C₁₋₆alkyl-O—C₁₋₆alkyl.

23. The compound of any one of Embodiments 1-18 or 22, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —CH₂CH₂OCH₃.

24. The compound of any one of Embodiments 1-18, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —C₁₋₆alkyl-OH.

25. The compound of any one of Embodiments 1-18, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —C₁₋₆alkyl=O.

26. The compound of any one of Embodiments 1-18, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —C₁₋₆alkyl-phenyl.

27. The compound of any one of Embodiments 1-18, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —C₁₋₆alkyl-O—SiR^(a)R^(b)R^(c).

28. The compound of any one of Embodiments 1-18, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —C₁₋₆alkyl-NR^(a)R^(b).

29. The compound of any one of Embodiments 1-18, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —C₁₋₆alkyl-C₃-C₆cycloalkyl.

30. The compound of any one of Embodiments 1-18, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —C₁₋₆alkyl-C₃-C₁₀heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from O, N or S.

31. The compound of any one of Embodiments 1-18, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is

32. The compound of any one of Embodiments 1-18, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is

33. The compound of any one of Embodiments 1-18, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is independently selected from —CH₃, —CH₂CH₂OCH₃,

34. The compound of any one of Embodiments 1-14, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R³ and R⁴, together with the atoms to which they are bonded, form a 5- to 12-membered ring, optionally containing a heteroatom selected from N, O or S in addition to the S and N atoms present in the ring, wherein the ring may optionally contain at least one double bond; and further wherein the ring is substituted with 0, 1, 2, or 3 R^(3A) substituents.

35. The compound of any one of Embodiments 1-14 or 34, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R³ and R⁴ together with the atoms to which they are attached form

36. The compound of any one of Embodiments 1-35, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵ is H or —C₁₋₆ alkyl.

37. The compound of any one of Embodiments 1-36, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵ is —CH₃.

38. The compound of any one of Embodiments 1-36, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵ is H.

39. The compound of any one of Embodiments 1-38, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶ is H or —C₁₋₆ alkyl.

40. The compound of any one of Embodiments 1-38, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶ is —CH₃.

41. The compound of any one of Embodiments 1-38, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶ is H.

42. The compound of any one of Embodiments 1-41, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein each of R^(4A), R^(5A), R^(6A), R^(7A) and R^(8A) is independently selected from H, OH, halo, or —C₁₋₆alkyl.

43 The compound of Embodiment 42, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein each of R^(4A), R^(5A), R^(6A), R^(7A) and R^(8A) is H.

44. The compound of any one of Embodiments 1, 2, or 4-43, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(7A) and R^(8A) are both H.

45. The compound of any one of Embodiments 1-44, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁷ and R⁸ are both H.

46. The compound of any one of Embodiments 1-45, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is independently selected from H, —C₁₋₆alkyl, —C₂₋₆alkenyl, or —C₁₋₆alkyl-O—C₁₋₆alkyl or —C₁₋₆haloalkyl.

47. The compound of any one of Embodiments 1-46, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is H.

48. The compound of any one of Embodiments 1-46, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is —CH₃.

49. The compound of any one of Embodiments 1-46, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is —CH₂CH₃.

50. The compound of any one of Embodiments 1-46, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is —CH₂CH(CH₃)₂.

51. The compound of any one of Embodiments 1-46, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is —CH₂CH₂OCH₃.

52. The compound of any one of Embodiments 1-46, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is —CF₃.

53. The compound of any one of Embodiments 1-52, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is selected from H, C₁₋₆haloalkyl, C₁₋₆alkyl, —C₂₋₆alkenyl —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b), —N═N═N, —C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂.

54. The compound of any one of Embodiments 1-53, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is —C₁₋₆alkyl.

55. The compound of any one of Embodiments 1-53, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is —C(═O)R^(a).

56. The compound of any one of Embodiments 1-53, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.

57. The compound of any one of Embodiments 1-53, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is a 3- to 12-membered monocyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O or N.

58. The compound of any one of Embodiments 1-53, 56 or 57, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein the 3- to 12-membered monocyclic heterocycloalkyl R^(9A) group can be unsubstituted or substituted with 1, 2, 3 or 4 R¹⁰ substituents independently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆alkynyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, or heterocycloalkyl group have from 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂.

59. The compound of any one of Embodiments 1-58, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein the 1, 2, 3 or 4 R¹⁰ substituents are independently selected from —C₁₋₆alkyl or a 3- to 12-membered monocyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.

60. The compound of any one of Embodiments 1-59, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹⁰ is —C₁₋₆alkyl.

61. The compound of any one of Embodiments 1-59, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹⁰ is a 3- to 12-membered monocyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.

62. The compound of any one of Embodiments 1-53, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is a 5- to 12-membered bicyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O or N.

63. The compound of any one of Embodiments 1-52, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is independently selected from —N═N═N,

64. The compound of any one of Embodiments 1-45, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ and R^(9A) together with Q, W, and the C to which W and Q are bonded, form a 3- to 12-membered monocyclic or bicyclic ring, optionally containing a heteroatom in addition to Q selected from N, O or S, wherein the ring may contain a double bond, wherein the ring may optionally include a C═O group, and further wherein the ring optionally may be substituted by 1, 2, or 3 R¹¹ substituents.

65. The compound of any one of Embodiments 1-45 and 64, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ and R^(9A) together with the atoms to which they are bonded form a structure selected from:

66. The compound of any one of Embodiments 1-9, 12-52 or 64, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein when W is C═O, then R^(9A) is

67. The compound of any one of Embodiments 1-11 or 14-66, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹ is H.

68. Another embodiment of the present invention comprises the compound of Embodiment 1, wherein the compound of Formula I′ has Formula II′:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof.

69. Another embodiment of the present invention comprises the compound of any one of Embodiments 1, 2, or 68, wherein the compound of Formula I′ has Formula II′a:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof.

70. The compound of any one of Embodiments 1, 2, 68, or 69, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is independently selected from H, —C₁₋₆alkyl, —C₁₋₆alkylhalo, —C₁₋₆alkyl-O—C₁₋₆alkyl, or —(CH₂CH₂O)_(n)R^(a), wherein the —C₁₋₆alkyl is unsubstituted or substituted with —OH, (═O), phenyl, —O—SiR^(a)R^(b)R^(c), —NR^(a)R^(b), a 3- to 12-membered cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from O, N or S.

71. The compound of any one of Embodiments 1, 2, 68-69, or 70, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —CH₃.

72. The compound of any one of Embodiments 1, 2, 68-69, or 70, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —CH₂CH₂OCH₃.

73. The compound of any one of Embodiments 1, 2, 68-71 or 72, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵ is H or —C₁₋₆ alkyl.

74. The compound of any one of Embodiments 1, 2, 68-71 or 72, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵ is —CH₃.

75. The compound of any one of Embodiments 1, 2, 68-71 or 72, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵ is H.

76. The compound of any one of Embodiments 1, 2, 68-74 or 75, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶ is H or —C₁₋₆ alkyl.

77. The compound of any one of Embodiments 1, 2, 68-75 or 76, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶ is —CH₃.

78. The compound of any one of Embodiments 1, 2, 68-75 or 76, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶ is H.

79. The compound of any one of Embodiments 1, 2, 68-77 or 78 or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is independently selected from H, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂.

80. The compound of any one of Embodiments 1, 2, 68-78 or 79, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is —CH₃.

81. The compound of any one of Embodiments 1, 2, 68-78 or 79, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is —CH₂CH₃.

82. The compound of any one of Embodiments 1, 2, 68-80 or 81, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is independently selected from H, C₁₋₆haloalkyl, C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b), —N═N═N, —C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂.

83. The compound of any one of Embodiments 1, 2, 68-81 or 82, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is —C₁₋₆alkyl.

84. The compound of any one of Embodiments 1, 2, 68-81 or 82, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is —C(═O)R^(a).

85. The compound of any one of Embodiments 1, 2, 68-81 or 82, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.

86. The compound of any one of Embodiments 1, 2, 68-82 or 85, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is a 3- to 12-membered monocyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O or N.

87. The compound of any one of Embodiments 1, 2, 68-82 or 85-86, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein the 3- to 12-membered monocyclic heterocycloalkyl R^(9A) group can be unsubstituted or substituted with 1, 2, 3 or 4 R¹⁰ substituents independently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂.

88. The compound of any one of Embodiments 1, 2, 68-82 or 85-86, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein the 1, 2, 3 or 4 R¹⁰ substituents are independently selected from —C₁₋₆alkyl or a 3- to 12-membered monocyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.

89. The compound of any one of Embodiments 1, 2, 68-82 or 85-88, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹⁰ is —C₁₋₆alkyl.

90. The compound of any one of Embodiments 1, 2, 68-82 or 85-88, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹⁰ is a 3- to 12-membered monocyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.

91. The compound of any one of Embodiments 1, 2, 68-82 or 85, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is a 5- to 12-membered bicyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O or N.

92. The compound of any one of Embodiments 1, 2, or 68-82, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is independently selected from:

93. Another embodiment of the present invention comprises the compound of Embodiment 1, wherein the compound of Formula I′ has Formula III′:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴, R⁵, R⁹ and R^(9A) are as defined above.

94. Another embodiment of the present invention comprises the compound of Embodiment 1, 2, or 93, wherein the compound of Formula I′ has Formula III′a:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof.

95. The compound of any one of Embodiments 1, 2, or 93-94, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is independently selected from H, —C₁₋₆alkyl, —C₁₋₆alkylhalo, —C₁₋₆alkyl-O—C₁₋₆alkyl, or —(CH₂CH₂O)_(n)R^(a), wherein the —C₁₋₆alkyl is unsubstituted or substituted with —OH, -(═O), phenyl, —O—SiR^(a)R^(b)R^(c), —NR^(a)R^(b), a 3- to 12-membered cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from O, N or S.

96. The compound of any one of Embodiments 1, 2, or 93-95, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —CH₃.

97. The compound of any one of Embodiments 1, 2, or 93-95, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —CH₂CH₂OCH₃.

98. The compound of any one of Embodiments 1, 2 or 93-97, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵ is H or —C₁₋₆alkyl.

99. The compound of any one of Embodiments 1, 2 or 93-98, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵ is —CH₃.

100. The compound of any one of Embodiments 1, 2 or 93-98, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵ is H.

101. The compound of any one of Embodiments 1, 2 or 93-100, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶ is H or —C₁₋₆alkyl.

102. The compound of any one of Embodiments 1, 2 or 93-101, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶ is —CH₃.

103. The compound of any one of Embodiments 1, 2 or 93-101, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶ is H.

104. The compound of any one of Embodiments 1, 2 or 93-103, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is independently selected from H, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂.

105. A compound of any one of Embodiments 1, 2 or 93-104, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is —CH₃.

106. A compound of any one of Embodiments 1, 2 or 93-104, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is —CH₂CH₃.

107. A compound of any one of Embodiments 1, 2 or 93-104, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is —H.

108. A compound of any one of Embodiments 1, 2 or 93-107, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is independently selected from H, C₁₋₆haloalkyl, C₁₋₆alkyl, —C₂₋₆alkenyl —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b), —N═N═N, —C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 10-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂.

109. The compound of any one of Embodiments 1, 2 or 93-108, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is —C₁₋₆alkyl.

110. The compound of any one of Embodiments 1, 2 or 93-108, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is —C(═O)R^(a).

111. The compound of any one of Embodiments 1, 2 or 93-108, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.

112. The compound of any one of Embodiments 1, 2, 93-108 or 111, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is a 3- to 12-membered monocyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O or N.

113. The compound of any one of Embodiments 1, 2, 93-108 or 112, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein the 3- to 12-membered monocyclic heterocycloalkyl R^(9A) group can be unsubstituted or substituted with from 1, 2, 3 or 4 R¹⁰ substituents independently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂.

114. The compound of any one of Embodiments 1, 2, 93-108 or 112-113, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein the 1, 2, 3 or 4 R¹⁰ substituents are independently selected from —C₁₋₆alkyl or a 3- to 12-membered monocyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.

115. The compound of any one of Embodiments 1, 2, 93-108 and 112-114, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹⁰ is —C₁₋₆alkyl.

116. The compound of any one of Embodiments 1, 2, 93-108 or 112-113, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹⁰ is a 3- to 12-membered monocyclic heterocycloalkyl group, wherein the heterocycloalkyl group has from 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.

117. The compound of any one of Embodiments 1, 2, 93-108 or 111, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is a 5- to 12-membered bicyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O or N.

118. The compound of any one of Embodiments 1, 2, or 93-108, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is independently selected from:

119. Another embodiment of the present invention comprises the compound of Embodiment 1, wherein the compound of Formula I′ has Formula IV′:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴, R⁵, R⁹ and R^(9A) are as defined above.

120. Another embodiment of the present invention comprises the compound of Embodiment 1, 2 or 119, wherein the compound of Formula I′ has Formula IV′a:

or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof.

121. The compound of any one of Embodiments 1, 2, or 119-120, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is independently selected from H, —C₁₋₆alkyl, —C₁₋₆alkylhalo, —C₁₋₆alkyl-O—C₁₋₆alkyl, or —(CH₂CH₂O)_(n)R^(a), wherein the —C₁₋₆alkyl is unsubstituted or substituted with —OH, -(═O), phenyl, —O—SiR^(a)R^(b)R^(c), —NR^(a)R^(b), a 3- to 12-membered cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from O, N or S.

122. The compound of any one of Embodiments 1, 2, or 119-121, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —CH₃.

123. The compound of any one of Embodiments 1, 2, or 119-121, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —CH₂CH₂OCH₃.

124. The compound of any one of Embodiments 1, 2, or 119-123, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵ is H or —C₁₋₆ alkyl.

125. The compound of any one of Embodiments 1, 2, or 119-124, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵ is —CH₃.

126. The compound of any one of Embodiments 1, 2, or 119-125, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵ is H.

127. The compound of any one of Embodiments 1, 2, or 119-126, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶ is H or —C₁₋₆ alkyl.

128. The compound of any one of Embodiments 1, 2, or 119-127, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶ is —CH₃.

129. The compound of any one of Embodiments 1, 2, or 119-127, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶ is H.

130. The compound of any one of Embodiments 1, 2, or 119-129, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is independently selected from H, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —C₂₋₆alkenyl, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂.

131. The compound of any one of Embodiments 1, 2, or 119-130, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is —CH₃.

132. The compound of any one of Embodiments 1, 2, or 119-130, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is —CH₂CH₃.

133. The compound of any one of Embodiments 1, 2, or 119-132, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is independently selected from H, C₁₋₆haloalkyl, C₁₋₆alkyl, —C₂₋₆alkenyl —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b), —N═N═N, —C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl group have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂.

134. The compound of any one of Embodiments 1, 2, or 119-133, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is —C₁₋₆alkyl.

135. The compound of any one of Embodiments 1, 2, or 119-113, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is —C(═O)R^(a).

136. The compound of any one of Embodiments 1, 2, or 119-133, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.

137. The compound of any one of Embodiments 1, 2, 119-133 or 136, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is a 3- to 12-membered monocyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O or N.

138. The compound of any one of Embodiments 1, 2, 119-133, or 136-137, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein the 3- to 12-membered monocyclic heterocycloalkyl R^(9A) group can be unsubstituted or substituted with 1, 2, 3 or 4 R¹⁰ substituents independently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂.

139. The compound of any one of Embodiments 1, 2, 119-133, or 136-138, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein the 1, 2, 3 or 4 R¹⁰ substituents are independently selected from —C₁₋₆alkyl or a 3- to 12-membered monocyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.

140. The compound of any one of Embodiments 1, 2, 119-133, or 136-139, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹⁰ is —C₁₋₆alkyl.

141. The compound of any one of Embodiments 1, 2, 119-133, or 136-139, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹⁰ is a 3- to 12-membered monocyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.

142. The compound of any one of Embodiments 1, 2, 119-133, or 136, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is a 5- to 12-membered bicyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O or N.

143. The compound of any one of Embodiments 68-70, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is independently selected from:

144. Another embodiment of the present invention comprises the compound of Embodiment 1, wherein the compound is selected from:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof.

145. The compound of embodiment 144 or the pharmaceutically acceptable salt thereof.

146. Another embodiment of the present invention comprises the compound of Embodiment 1, wherein the compound is selected from:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof.

147. The compound of embodiment 146 or the pharmaceutically acceptable salt thereof.

148. Another embodiment of the present invention comprises a pharmaceutical composition comprising the compound of any one of Embodiments 1-147 or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

149. Another embodiment of the present invention comprises a method of treating cancer, the method comprising: administering to a patient in need thereof a therapeutically effective amount of the compound of any of Embodiments 1-147 or the pharmaceutically acceptable salt thereof.

150. The method of Embodiment 149, wherein the cancer is a hematologic malignancy.

151. The method of Embodiment 149, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia, and acute myelogenous leukemia.

152. The method of Embodiment 149, wherein the cancer is multiple myeloma.

153. The method of Embodiment 149, further comprising administering to the patient in need thereof a therapeutically effective amount of an additional pharmaceutically active compound.

154. The method of Embodiment 153, wherein the additional pharmaceutically active compound is carfilzomib.

155. The method of Embodiment 153, wherein the additional pharmaceutically active compound is venetoclax.

156. The method of Embodiment 153, wherein the additional pharmaceutically active compound is cytarabine.

157. Another embodiment of the present invention comprises the use of a compound according to any one of Embodiments 1-147 for treating cancer in a subject.

158. Another embodiment of the present invention comprises the compound according to any one of Embodiments 1-147 in the preparation of a medicament for treating cancer.

159. The compound according to Embodiment 158, wherein the cancer is a hematologic malignancy.

160. The compound according to Embodiment 158, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia, and acute myelogenous leukemia.

161. The compound according to Embodiment 158, wherein the cancer is multiple myeloma.

162. The compound according to Embodiment 158, wherein the cancer is acute myelogenous leukemia.

163. The compound according to Embodiment 158, wherein the cancer is non-Hodgkin's lymphoma.

Embodiments B

The embodiments listed below are presented in numbered form for convenience and for ease and clarity of reference in referring back to multiple embodiments.

In a first embodiment, the present invention comprises a compound of Formula I:

a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, wherein:

Z is C or N;

Q is O, S, CR^(WA)R^(WB), or NR^(a)R^(b);

W is CR^(WA)R^(WB), —C═O, or is absent;

R^(WA) and R^(WB) are independently selected from H, —C₁₋₃alkyl, —C₂₋₃alkenyl, —C₂₋₃alkynyl, halo, —OH, or —O—C₁₋₃alkyl;

b, represented by the symbol

, is a single or double chemical bond which may be cis or trans;

R¹ is independently selected from H, halo, C₁₋₆alkylhalo, C₁₋₆alkyl, C₂₋₆alkenyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), or —C(═O)NR^(a)R^(b);

R² is selected from H, halo, C₁₋₆haloalkyl, C₁₋₆alkyl, O—C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkenylene, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), —C(═O)NR^(a)R^(b), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl or heterocycloalkyl group have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O or SO₂;

R³ is selected from H, —C₁₋₆alkylhalo, —C₁₋₆alkyl, —C₂₋₆alkenyl, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a), —C(═O)OR^(a), or —C(═O)NR^(a)R^(b);

each of R^(2B), R^(2C), R⁴, R⁵, R⁶, R⁷, and R⁸ is independently selected from H, halo, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), —C(═O)NR^(a)R^(b), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

alternatively R³ and R⁴ together with the atoms to which they are bonded may form a 5- to 12-membered ring, optionally containing a heteroatom selected from a N, O or S atom, in addition to the S and N atoms present in the ring, wherein the ring may optionally contain at least one double bond; and the ring may be substituted with 0, 1, 2, or 3 R^(3A) substituents;

wherein R^(3A) is selected from H, halo, —OH, C₁₋₆haloalkyl, C₁₋₆alkyl, O—C₁₋₆alkyl, C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), or —C(═O)NR^(a)R^(b);

each of R^(4A), R^(5A), R^(6A), R^(7A), and R^(8A) is independently selected from H, OH, halo, or —C₁₋₆alkyl;

R^(7A) and R^(8A) are absent when b is a double chemical bond;

alternatively R⁷ and R⁸ together with the atoms to which they are bonded may form a 3- to 12-membered ring, wherein the ring may optionally contain at least one double bond;

R⁹ is independently selected from H, OH, -(═O), —C₁₋₆haloalkyl, —C₁₋₆alkyl, —C₁₋₆alkenylene, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —C₁₋₆alkyl-O—C₁₋₆alkyl, cyano, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl or heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl group may include a C═O group, and further wherein the spiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O or SO₂;

R^(9A) is independently selected from H, —OH, halo, cyano, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁₋₆alkenylene, —(CH₂CH₂O)_(n)R^(a), —P(═O)OR^(a)OR^(b), —CSR^(a), —CS(═O)R^(a), —SR^(a), —SOR^(a), —OSO₂R^(a), —SO₂R^(a), —(CH₂CH₂O)_(n)CH₃, -(═O), —C(═O), —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —CH₂—NR^(a)R^(b), —NR^(a)R^(b), —C₁₋₆alkyl-O—C₁₋₆alkyl, —OC₁₋₆alkyl, —O—C₁₋₆alkyl-O—C₁₋₆alkyl, phenyl, a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may contain a double bond and may contain a C═O group, and further wherein the spiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O or SO₂;

wherein R^(9A) is not H when W is absent;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of the R^(9A) substituent can be unsubstituted or substituted with 1, 2, 3 or 4 R¹⁰ substituents independently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆alkynyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 0, 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

alternatively R⁷ and R^(9A) together with the atoms to which they are bonded may form a 3- to 12-membered ring, wherein the ring may optionally contain at least one double bond;

alternatively R⁹ and R^(9A) together with Q, W, and the C to which W and Q are bonded, may form a 3- to 12-membered monocyclic or bicyclic ring, optionally containing a heteroatom in addition to Q that is selected from N, O or S, wherein the ring may contain a double bond, wherein the ring may optionally include a C═O group, and further wherein the ring optionally may be substituted by 1, 2, or 3 R¹¹ substituents;

R¹¹ is independently selected from H, —OH, halo, —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —NR^(c)R^(d), —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(c), —C(═O)OR^(c), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl group may include a double bond, and wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl group may include a C═O group, and further wherein the spiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O or SO₂;

wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and the —OC₁₋₆alkyl of any of the R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R^(4A), R^(5A), R^(6A), R^(7A), R^(8A), R^(9A), R^(WA) and R^(WB) substituents is unsubstituted or substituted by 1, 2 or 3 R¹² substituents independently selected from OH, —OC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, halo, —O-haloC₁₋₆alkyl, —CN, —NR^(a)R^(b), —(NR^(a)R^(b)R^(c))_(n), —OSO₂R^(a), —SO₂R^(a), —(CH₂CH₂O)_(n)CH₃, -(═O), —C(═O), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —O—SiR^(a)R^(b)R^(c), —SiR^(a)R^(b)R^(c), —O-(3- to 10-membered heterocycloakyl), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O or SO₂;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl group of any of the R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9A), R¹⁰, R¹¹, R¹², R^(WA) and R^(WB) substituents can be unsubstituted or substituted with 1, 2, 3 or 4 R¹³ substituents independently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups of R¹³ have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, and spiroheterocycloalkyl groups of R¹³ or the heterocycloalkyl group of R¹³ may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂;

wherein each R^(a), R^(b), R^(c), and R^(d) is independently hydrogen, OH, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₁₋₆alkyl-NR¹⁴R¹⁴, —NR¹⁴R¹⁴, —SO₂R¹⁴, —(CH₂CH₂O)_(n)CH₃, -(═O), —C(═O)R¹⁴, —OC(═O)R¹⁴, —C(═O)OR¹⁴, —C(═O)NR¹⁴R¹⁴, —C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, benzyl, phenyl, —C₁₋₆alkyl-C(═O)OH, —C₁₋₆alkyl-C(═O)—O—C₁₋₆alkyl, —C₁₋₆alkyl-cycloalkyl, —C₁₋₆alkyl-heterocycloalkyl, —C₁₋₆alkyl-6- to 10-membered aryl, —C₁₋₆alkyl-6- to 10-membered heteroaryl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, where the heteroaryl, spiroheterocycloalkyl, heterocycloalkyl group or the —C₁₋₆alkyl-heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, heterocycloalkyl, group of R^(a), R^(b), R^(c), and R^(d) or the heterocycloalkyl group or the —C₁₋₆alkyl-heterocycloalkyl group may include a double bond and may contain a C═O group, and the spiroheterocycloalkyl, or heterocycloalkyl may include a S═O or SO₂;

the alkyl, aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, or heterocycloalkyl group of R^(a), R^(b), R^(c), and R^(d) and the heterocycloalkyl group of the —C₁₋₆alkyl-heterocycloalkyl group of R^(a), R^(b), R^(c), and R^(d) can be unsubstituted or substituted with 1, 2, 3, or 4 R¹⁴ substituents, wherein each R¹⁴ is independently selected from H, —OH, —N═N═N, halo, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, phenyl, tolyl, —C(═O)C₁₋₆alkyl, —C(═O)O—C₁₋₆alkyl, N(CH₃)₂ or —SO₂—N(CH₃)₂; and

wherein n is independently in each instance an integer of 1, 2, 3 or 4.

2. Another embodiment of the present invention comprises the compound of embodiment 1, wherein the compound has the Formula II:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof.

3. Another embodiment of the present invention comprises a compound of any of embodiments 1 or 2, wherein the compound has the Formula IIa:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof.

4. The compound of any one of embodiments 1-3, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein Q is O, NR^(a)NR^(b), or S.

5. The compound of any one of embodiments 1-4, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein Q is O.

6. The compound of any one of embodiments 1-5, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein W is CR^(WA)R^(WB), —C═O, or is absent.

7. The compound of embodiment 5, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein W is CR^(WA)R^(WB).

8. The compound of embodiment 5, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein W is absent.

9. The compound of any one of embodiments 1-7, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(WA) and R^(WB) are independently selected from H, (═O), —C₁₋₃alkyl, —C₂₋₃alkenyl, —C₂₋₃alkynyl, halo, —OH, or —O—C₁₋₃alkyl.

10. The compound of embodiment 9, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(WA) and R^(WB) are both H.

11. The compound of embodiment 9, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(WA) is —CH₃.

12. The compound of embodiment 9, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(WB) is —CH₃.

13. The compound of embodiment 9, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(WA) is —OH and R^(WB) is H.

14. The compound of any one of embodiments 1-13, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹ is halo.

15. The compound of embodiment 14, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹ is Cl.

16. The compound of any one of embodiments 1-15, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R³ is selected from H and —C₁₋₆alkyl.

17. The compound of embodiment 16, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R³ is H.

18. The compound of any one of embodiments 1-17, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is independently selected from H, —C₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OSO₂CH₃, —C₁₋₆alkyl-phenyl, or —C₁₋₆alkyl-(5-6 membered heterocycloalkyl, having one or two heteroatoms independently selected from N or O).

19. The compound of any one of embodiments 1-18, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is independently selected from H, —CH₃, —CH₂CH₃,

20. The compound of embodiment 19, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —CH₃.

21. The compound of any one of embodiments 1-20, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵ is selected from H or —C₁₋₆alkyl.

22. The compound of embodiment 21, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵ is —CH₃.

23. The compound of any one of embodiments 1-22, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶ is selected from H or —C₁₋₆alkyl.

24. The compound of embodiment 23, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶ is H.

25. The compound of any one of embodiments 1-24, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is independently selected from H, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-(5-6 membered heterocycloalkyl), wherein the heterocycloalkyl has one or two heteroatoms independently selected from N or O, or —C₁₋₆alkyl-phenyl, wherein the phenyl of the —C₁₋₆alkyl-phenyl of the R⁹ groups is unsubstituted or substituted with 1 or 2 R¹³ substituents selected from halo or —C₁₋₆alkyl-O—C₁₋₆alkyl.

26. The compound of embodiment 25, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is independently selected from H, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, CH₂CH₂OCH₃, CH₂CF₃,

27. The compound of embodiment 26, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is H.

28. The compound of embodiment 26, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is —C₁₋₆alkyl.

29. The compound of embodiment 26, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is —CH₃.

30. The compound of embodiment 26, wherein R⁹ is

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof.

31. The compound of any one of embodiments 1-24, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein alternatively R⁹ and R^(9A) together with Q, W, and the C to which W and Q are bonded, may form a 3- to 12-membered monocyclic or bicyclic ring, optionally containing a heteroatom in addition to Q that is selected from N, O or S, wherein the ring may contain a double bond, wherein the ring may optionally include a C═O group.

32. The compound of embodiment 31, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ and R^(9A) together with Q, W and the C to which Q and W are bonded form

33. The compound of any one of embodiments 1-30, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is independently selected from H, OH, —C₁₋₆alkyl, —C₂-C₆ alkenyl, —C₂₋₆alkynyl; —OC₁₋₆alkyl, —CH₂—NR^(a)R^(b), —C(═O)NR^(a)R^(b), -(═O), —C(═O), C(═O)OR^(a), —C(═O)R^(a), cyano, —C₁₋₆haloalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —O—C₁₋₆alkyl-O—C₁₋₆alkyl, —P(═O)OR^(a)OR^(b), —SR^(a), —OSO₂R^(a), —SOR^(a), —SO₂R^(a), a 6- to 12-membered aryl or heteroaryl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered unsubstituted monocyclic or bicyclic heterocycloalkyl group, wherein the aryl, heteroaryl, or heterocycloalkyl group can have from 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl and the heterocycloalkyl group may contain a double bond and further wherein the cycloalkyl and the heterocycloalkyl group may contain a C═O group;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, group of the R^(9A) substituent can be unsubstituted or substituted with from 1, 2, 3 or 4 R¹⁰ substituents independently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, cyano, —C(═O)OR^(c), a 6- to 10-membered aryl, or —SO₂R^(c);

wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and the —OC₁₋₆alkyl of any of the R^(9A) and R¹⁰ substituents is unsubstituted or substituted by 1, 2 or 3 R¹² substituents independently selected from OH, halo, -(═O), —OC₁₋₆alkyl, —C₁₋₆alkyl, —NR^(a)R^(b), —SiR^(a)R^(b)R^(c), a 6- to 12-membered aryl or heteroaryl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, or heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl or heterocycloalkyl groups may include a C═O group, and further wherein the heterocycloalkyl group may include a S═O or SO₂;

wherein the —C₁₋₆alkyl groups of the R¹⁰ substituents is unsubstituted or substituted by 1, 2 or 3 R¹² substituents of —OC₁₋₆alkyl;

wherein the heterocycloalkyl groups of R¹² substituents can be unsubstituted or substituted with from 1, 2, 3 or 4 R¹³ substituents independently selected from —NR^(c)R^(d), or —C₁₋₆alkyl;

wherein each R^(a), R^(b), R^(c) and R^(d) is independently hydrogen, OH, —C₁₋₆alkyl, —(CH₂CH₂O)_(n)CH₃, —NR¹⁴R¹⁴, —C₁₋₆alkyl-NR¹⁴R¹⁴, phenyl, —C₁₋₆alkyl-C(═O)OH, —C₁₋₆alkyl-C(═O)—O—C₁₋₆alkyl, —C₁₋₆alkyl-3- to 12-membered cycloalkyl, —C₁₋₆alkyl-3- to 12-membered heterocycloalkyl, —C₁₋₆alkyl-6- to 12-membered heteroaryl, a 6- to 12-membered aryl or heteroaryl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl group, heterocycloalkyl groups of R^(a), R^(b), R^(c), and R^(d) or the heterocycloalkyl group of the —C₁₋₆alkyl-heterocycloalkyl group of R^(a), R^(b), R^(c), and R^(d) has from 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl and heterocycloalkyl groups of R^(a), R^(b), R^(c), and R^(d) and the heterocycloalkyl group of the —C₁₋₆alkyl-heterocycloalkyl groups of R^(a), R^(b), R^(c), and R^(d) may include a double bond, and further wherein the cycloalkyl and heterocycloalkyl groups of R^(a), R^(b), R^(c), and R^(d) and the heterocycloalkyl group of the —C₁₋₆alkyl-heterocycloalkyl groups of R^(a), R^(b), R^(c), and R^(d) may contain a C═O group;

the alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl groups of R^(a), R^(b), R^(c), and R^(d) or the heterocycloalkyl groups of the —C₁₋₆alkyl-heterocycloalkyl groups of R^(a), R^(b), R^(c), and R^(d) can be unsubstituted or substituted with from 1, 2, 3, or 4 R¹⁴ substituents, wherein each R¹⁴ is independently selected from H, OH, halo, —C₁₋₆alkyl, N(CH₃)₂, —C₁₋₆haloalkyl, C(═O)CH₃, —C(═O)OCH₃, or —C₁₋₆alkyl-O—C₁₋₆alkyl;

alternatively R^(a) and R^(b) together with the atoms to which they are bonded may form a 4- to 12-membered monocyclic or bicyclic ring, optionally containing a heteroatom selected from N, O or S atom, which may contain a double bond; and

wherein n is independently in each instance an integer from 1, 2, 3 or 4.

34. The compound of any one of embodiments 1-23, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is independently selected from H, —CH₃, OH,

35. The compound of embodiment 34, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is H.

36. The compound of embodiment 34, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is —CH₃.

37. The compound of embodiment 34, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is —OH.

38. The compound of embodiment 34, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is

39. The compound of embodiment 34, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is

40. The compound of embodiment 34, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is

41. The compound of embodiment 34, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is

42. The compound of embodiment 34, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is

43. The compound of embodiment 34, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is

44. The compound of embodiment 34, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is

45. The compound of embodiment 34, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is

46. The compound of embodiment 34, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is

47. The compound of embodiment 34, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is

48. The compound of embodiment 34, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is

49 Another embodiment of the present invention comprises a compound of embodiment 1, wherein the compound has the Formula III:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof.

50. Another embodiment of the present invention comprises a compound of any one of embodiments 1 or 49, wherein the compound has the Formula IIIa:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof.

51. The compound of any one of embodiments 1, or 49-50, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein Q is O, —CR^(a)R^(b), or —NR^(a)R^(b).

52. The compound of embodiment 51, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein Q is O.

53. The compound of embodiment 52, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein Q is —CH₂.

54. The compound of embodiment 52, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein Q is —NR^(a)R^(b).

55. The compound of any one of embodiments 1, or 49-54, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein W is CR^(WA)R^(WB), —C═O, or is absent.

56. The compound of embodiment 55, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein W is CR^(WA)R^(WB).

57. The compound of embodiment 55, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein W is absent.

58. The compound of any one of embodiments 1, or 49-56, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(WA) and R^(WB) are independently selected from H, —C₁₋₃alkyl, —C₁₋₃alkenyl, —C₁₋₃alkynyl, halo, —OH, or —O—C₁₋₃alkyl.

59. The compound of embodiment 58, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(WA) and R^(WB) are both H.

60. The compound of embodiment 58, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(WA) is —CH₃.

61. The compound of embodiment 58, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein at least one of R^(WA) and R^(WB) is H.

62. The compound of embodiment 58, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(WA) is —OH and R^(WB) is H.

63. The compound of any one of embodiments 1, or 49-62, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹ is halo.

64. The compound of embodiment 63, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹ is Cl.

65. The compound of any one of embodiments 1, or 49-64, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R³ is H.

66. The compound of any one of embodiments 1, or 49-65, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is independently selected from H or —C₁₋₆alkyl.

67. The compound of embodiment 66, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —CH₃.

68. The compound of any one of embodiments 1, or 49-67, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵ is selected from H or —C₁₋₆alkyl.

69. The compound of embodiment 68, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵ is —CH₃.

70. The compound of any one of embodiments 1, or 49-69, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶ is H.

71. The compound of any one of embodiments 1, or 49-70, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁷ is selected from H or —NR^(a)R^(b).

72. The compound of embodiment 71, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁷ is H.

73. The compound of any one of embodiments 1, or 49-73, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁸ is selected from H or —C₁₋₆alkyl.

74. The compound of embodiment 73, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁸ is H.

75. The compound of any one of embodiments 1, or 49-70, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein alternatively R⁷ and R⁸ together with the atoms to which they are bonded may form a 3- to 12-membered ring.

76. The compound of any one of embodiments 1, 49-70, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein alternatively R⁷ and R^(9A) together with the atoms to which they are bonded may form a 3- to 12-membered ring, wherein the ring may optionally contain at least one double bond.

77. The compound of any one of embodiments 1, 49-76, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is independently selected from H, —OH, -(═O), —C₁₋₆alkyl, cyano, —C(═O)—C₁₋₆alkyl, —C(═O)-phenyl, —C₁₋₆alkyl-O— C₁₋₆alkyl, —C₁₋₆alkyl-(5-10 membered mono or bicyclic heterocycloalkyl), wherein the heterocycloalkyl may contain one, two, three or four heteroatoms independently selected from N or O.

78. The compound of any one of embodiments 1, or 49-75, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein alternatively R⁹ and R^(9A) together with Q, W and the C to which Q and W are bonded, may form a 3- to 12-membered monocyclic or bicyclic ring, optionally containing a heteroatom in addition to Q selected from N, O or S atom, the ring may contain a double bond, the ring may optionally include a C═O group, and the ring optionally may be substituted with 0, 1, 2, or 3 R¹¹ substituents;

wherein R¹¹ is selected from H, halo, —OH, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —C(═O)R^(c), —C(═O)NR^(c)R^(d), —NR^(c)R^(d), a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, where the heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the heterocycloalkyl groups may include a double bond, and wherein the heterocycloalkyl groups may contain a C═O group; and further wherein the heterocycloalkyl groups may be unsubstituted or substituted with one or more —C₁₋₆alkyl.

79. The compound of any one of embodiments 1, 49-75 or 77, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is independently selected from H, —OH, —C₁₋₆alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, —C₁₋₆alkyl, —C(═O), -(═O), —C(═O)R^(a), cyano, —C₁₋₆alkyl-O— C₁₋₆alkyl, —O— C₁₋₆alkyl-O—C₁₋₆alkyl, —OR^(a), —CSR^(a), —CS(═O)R^(a), —SOR^(a), —NR^(a)R^(b), —C(═O)NR^(a)R^(b), phenyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and the cycloalkyl and heterocycloalkyl groups may contain a double bond and wherein the cycloalkyl and heterocycloalkyl groups may contain a C═O group, and further wherein the heterocycloalkyl groups may include a S═O or SO₂;

wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups of the R^(9A) substituent can be unsubstituted or substituted with from 1, 2, 3 or 4 R¹⁰ substituents independently selected from halo, —NR^(c)R^(d), or —C₁₋₆alkyl;

wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and the —OC₁₋₆alkyl of any of the R^(9A) and R¹⁰ substituents is unsubstituted or substituted by 1, 2 or 3 R¹² substituents independently selected from OH, halo, -(═O), —OC₁₋₆alkyl, —C₁₋₆alkyl, —NR^(a)R^(b), —SiR^(a)R^(b)R^(c), a 6- to 12-membered aryl or heteroaryl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, where the heteroaryl or heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and the heterocycloalkyl groups may include a C═O group.

80. The compound of any one of embodiments 1, 49-76, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is independently selected from H, —OH, —CH₃, —CH₂CH₃, —C(═O)CH₃, —CH₂C(═O)OCH₂CH₃,

81. The compound of embodiment 80, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is H.

82. The compound of embodiment 80, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is —CH₃.

83. The compound of any one of embodiments 1, 49-75, or 77-80, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is independently selected from H, —OH, —CH₃, —CH₂CH₃, —OCH₂C(═O)OCH₂CH₃,

84. The compound of embodiment 83, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is H.

85. The compound of embodiment 83, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is —C₁₋₆alkyl.

86. The compound of embodiment 83, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is —CH₃.

87. The compound of embodiment 83, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is

88. The compound of any one of embodiments 1, 49-75 and 78, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein alternatively R⁹ and R^(9A) together with the atoms to which they are bonded may form a 5- to 12-membered monocyclic or bicyclic ring, optionally containing a heteroatom in addition to Q selected from N, O or S atom, further wherein the 5-12 membered ring may contain a double bond.

89. The compound of embodiment 88, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ and R^(9A) together with Q, W and the C to which Q and W are bonded form

90. Another embodiment of the present invention comprises a compound, wherein the compound has a structure selected from:

or a stereoisomer thereof; a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof.

91. Another embodiment of the present invention comprises a compound, wherein the compound has a structure selected from.

or a stereoisomer thereof; a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof.

92. The compound of embodiment 91 or the pharmaceutically acceptable salt thereof.

93. Another embodiment of the present invention comprises a pharmaceutical composition comprising the compound of any one of embodiments 1-92 or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

94. Another embodiment of the present invention comprises a method of treating cancer, the method comprising: administering to a patient in need thereof a therapeutically effective amount of the compound of any of embodiments 1-92 or a pharmaceutically acceptable salt thereof.

95. The method of embodiment 94, wherein the cancer is a hematologic malignancy.

96. The method of embodiment 94, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia, and acute myelogenous leukemia.

97. The method of embodiment 94, wherein the cancer is multiple myeloma.

98. The method of embodiment 94, further comprising administering to the patient in need thereof a therapeutically effective amount of an additional pharmaceutically active compound.

99. The method of embodiment 98, wherein the additional pharmaceutically active compound is carfilzomib.

100. The method of embodiment 98, wherein the additional pharmaceutically active compound is venetoclax.

101. The method of embodiment 98, wherein the additional pharmaceutically active compound is cytarabine.

102. Another embodiment of the present invention comprises a use of a compound according to any one of Embodiments 1-92 for treating cancer in a subject.

103. Another embodiment of the present invention comprises a compound according to any one of Embodiments 1-92 in the preparation of a medicament for treating cancer.

104. The compound according to Embodiment 103, wherein the cancer is a hematologic malignancy.

105. The compound according to embodiment 102, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia, and acute myelogenous leukemia.

106. The compound according to Embodiment 102, wherein the cancer is multiple myeloma.

107. The compound according to Embodiment 102, wherein the cancer is acute myelogenous leukemia.

108. The compound according to Embodiment 102, wherein the cancer is non-Hodgkin's lymphoma. Another embodiment of the present invention is directed to a method of inhibiting myeloid cell leukemia 1 protein (Mcl-1) of a cell comprising contacting the cell with the compound of Formula I in an effective amount to inhibit the Mcl-1, in conjunction with any of the above or below embodiments. In one embodiment, the contacting is in vitro. In another embodiment, the contacting is in vivo. In one embodiment, the contacting comprises administering the compound to a subject. In one embodiment, the administering is oral, parenteral, via injection, via inhalation, transdermal, or transmucosal. In one embodiment, the subject suffers from cancer.

One embodiment of the present invention is directed to a method of the treatment of cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of Formula I or a pharmaceutical composition comprising the compound of Formula I, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, in conjunction with any of the above or below embodiments. In one embodiment, the cancer is a hematologic malignancy. In one embodiment, the cancer is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia, and acute myelogenous leukemia. In one embodiment, the cancer is multiple myeloma. In another embodiment, the method further comprises the step of administering to the patient in need thereof a therapeutically effective amount of at least one additional pharmaceutically active compound. In one embodiment, the additional pharmaceutically active compound is carfilzomib, in conjunction with any of the above embodiments.

The methods provided herein include the manufacture and use of pharmaceutical compositions, which include one or more of the compounds provided herein. Also included are the pharmaceutical compositions themselves.

In some Claims, a compound provided herein may contain one or more acidic functional groups and, thus, is capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic inorganic and organic base addition salts of a compound provided herein. These salts can likewise be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).

Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives and antioxida

Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

A pharmaceutical composition may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include tonicity-adjusting agents, such as sugars and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of one or more compounds provided herein, it is desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. For example, delayed absorption of a parenterally administered compound can be accomplished by dissolving or suspending the compound in an oil vehicle.

The compounds of the present invention are administered to a patient in a therapeutically effective amount. The compounds can be administered alone or as part of a pharmaceutically acceptable composition or formulation. In addition, the compounds or compositions can be administered all at once, as for example, by a bolus injection, multiple times, such as by a series of tablets, or delivered substantially uniformly over a period of time, as for example, using transdermal delivery. The dose of the compound or composition can be varied over time. All combinations, delivery methods and administration sequences are contemplated.

The compounds of the present invention and in some Claims, other additional pharmaceutically active compounds, can be administered to a patient either orally, rectally, parenterally, (for example, intravenously, intramuscularly, or subcutaneously) intracistemally, intravaginally, intraperitoneally, intravesically, locally (for example, powders, ointments or drops), or as a buccal or nasal spray. All methods that are used by those skilled in the art to administer a pharmaceutically active agent are contemplated.

Compositions prepared as described herein can be administered in various forms, depending on the disorder to be treated and the age, condition, and body weight of the patient, as is well known in the art. For example, where the compositions are to be administered orally, they may be formulated as tablets, capsules, granules, powders, or syrups; or for parenteral administration, they may be formulated as injections (intravenous, intramuscular, or subcutaneous), drop infusion preparations, or suppositories. For application by the ophthalmic mucous membrane route, they may be formulated as eye drops or eye ointments. These formulations can be prepared by conventional means in conjunction with the methods described herein, and, if desired, the active ingredient may be mixed with any conventional additive or excipient, such as a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent, or a coating agent.

Formulations suitable for oral administration may be in the form of capsules (e.g., gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, troches, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert matrix, such as gelatin and glycerin, or sucrose and acacia) and/or as mouthwashes, and the like, each containing a predetermined amount of a compound provided herein as an active ingredient. A composition may also be administered as a bolus, electuary, or paste. Oral compositions generally include an inert diluent or an edible carrier.

Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of an oral composition. In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, and the like), the active ingredient can be mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, cyclodextrins, lactose, sucrose, saccharin, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, microcrystalline cellulose, gum tragacanth, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato, corn, or tapioca starch, alginic acid, Primogel, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, Sterotes, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof, (10) a glidant, such as colloidal silicon dioxide; (11) coloring agents; and (12) a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols, and the like.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of a powdered compound moistened with an inert liquid diluent.

Tablets, and other solid dosage forms, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes, microspheres, and/or nanoparticles. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

Suspensions, in addition to the active compound(s) may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Pharmaceutical compositions suitable for parenteral administration can include one or more compounds provided herein in combination with one or more pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

In one Claim, the IV formulation consists of a composition containing hydroxypropyl beta cyclodextrin within a pH range between 8-10 as a buffered or unbuffered solution. The IV formulation can be formulated as a sterile solution ready for injection, a sterile solution ready for dilution into an IV admixture or a sterile solid for reconstitution. The API in the IV formulation may exist as a free acid/base or an in situ salt.

Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions provided herein include water for injection (e.g., sterile water for injection), bacteriostatic water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol such as liquid polyethylene glycol, and the like), sterile buffer (such as citrate buffer), and suitable mixtures thereof, vegetable oils, such as olive oil, injectable organic esters, such as ethyl oleate, and Cremophor EL™ (BASF, Parsippany, N.J.). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

The composition should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are freeze-drying (lyophilization), which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Injectable depot forms can be made by forming microencapsule or nanoencapsule matrices of a compound provided herein in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes, microemulsions or nanoemulsions, which are compatible with body tissue.

For administration by inhalation, the compounds can be delivered in the form of an aerosol spray from a pressured container or dispenser that contains a suitable propellant (e.g., a gas such as carbon dioxide) or a nebulizer. Such methods include those described in U.S. Pat. No. 6,468,798. Additionally, intranasal delivery can be accomplished, as described in, inter alia, Hamajima et al., Clin. Immunol. Immunopathol., 88(2), 205-10 (1998). Liposomes (e.g., as described in U.S. Pat. No. 6,472,375, which is incorporated herein by reference in its entirety), microencapsulation and nanoencapsulation can also be used. Biodegradable targetable microparticle delivery systems or biodegradable targetable nanoparticle delivery systems can also be used (e.g., as described in U.S. Pat. No. 6,471,996, which is incorporated herein by reference in its entirety).

Systemic administration of a therapeutic compound as described herein can also be by transmucosal or transdermal means. Dosage forms for the topical or transdermal administration of a compound provided herein include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

The ointments, pastes, creams, and gels may contain, in addition to one or more compounds provided herein, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound provided herein, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

A compound provided herein can be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation, or solid particles containing a compound or composition provided herein. A nonaqueous (e.g., fluorocarbon propellant) suspension could be used. In some Claims, sonic nebulizers are used because they minimize exposing the agent to shear, which can result in degradation of the compound.

Ordinarily, an aqueous aerosol can be made by formulating an aqueous solution or suspension of the agent together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular composition, but typically include nonionic surfactants (TWEEN® (polysorbates), PLURONIC® (poloxamers), sorbitan esters, lecithin, CREMOPHOR® (polyethoxylates)), pharmaceutically acceptable co-solvents such as polyethylene glycol, innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

Transdermal patches have the added advantage of providing controlled delivery of a compound provided herein to the body. Such dosage forms can be made by dissolving or dispersing the agent in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

The pharmaceutical compositions can also be prepared in the form of suppositories or retention enemas for rectal and/or vaginal delivery. Formulations presented as a suppository can be prepared by mixing one or more compounds provided herein with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, glycerides, polyethylene glycol, a suppository wax or a salicylate, which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent. Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate.

In one claim, the therapeutic compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such formulations can be prepared using standard techniques, or obtained commercially (e.g., from Alza Corporation and Nova Pharmaceuticals, Inc). Liposomal suspensions (including liposomes targeted to selected cells with monoclonal antibodies to cellular antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811, which is incorporated herein by reference in its entirety for all purposes.

The compounds of the present invention are used in the treatment of diseases, disorders or symptoms mediated by Mcl-1 inhibition. Examples of diseases, disorders or symptoms mediated by Mcl-1 inhibition include, but are not limited to, cancers. Non-limiting examples of cancers include breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia, and acute myelogenous leukemia.

The cancers can include carcinomas (originating in the outer layer of cells of the skin and internal membranes, e.g., breasts, kidneys, lungs, skin); sarcomas (arising from connective tissue such as bone, muscle, cartilage, and blood vessels), and hematologic malignancies (e.g., lymphomas and leukemias, which arise in the blood or blood-forming organs such as the spleen, lymph nodes, and bone marrow). Cancer cells can include, for example, tumor cells, neoplastic cells, malignant cells, metastatic cells, and hyperplastic cells.

In an Claim, the disease, disorder or symptom is a hyperproliferative disorder, e.g., a lymphoma, leukemia, carcinoma (e.g., renal, breast, lung, skin), multiple myeloma, or a sarcoma. In one Claim, the leukemia is acute myeloid leukemia. In one Claim, the hyperproliferative disorder is a relapsed or refractory cancer.

Actual dosage levels of the active ingredients in the pharmaceutical compositions provided herein may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

The specific dosage and dosage range depends on a number of factors, including the requirements of the patient, the severity of the condition or disease being treated, the pharmacokinetic characteristics of the compound(s) employed, and the route of administration. In some Claims, the compositions provided herein can be provided in an aqueous solution containing about 0.1-10% w/v of a compound disclosed herein, among other substances, for parenteral administration. Typical dose ranges can include from about 0.01 to about 50 mg/kg of body weight per day, given in 1-4 divided doses. Each divided dose may contain the same or different compounds. The dosage will be a therapeutically effective amount depending on several factors including the overall health of a patient, and the formulation and route of administration of the selected compound(s).

Dosage forms or compositions containing a compound as described herein in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared. Methods for preparation of these compositions are known to those skilled in the art. The contemplated compositions may contain about 0.001%-100% active ingredient, in one Claim from about 0.1 to about 95%, in another Claim from about 75 to about 85%. Although the dosage will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration and the form of the drug, in general, a daily dosage of from about 0.01 to about 3,000 mg of the compound is recommended for an adult human patient, and this may be administered in a single dose or in divided doses. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.

The pharmaceutical composition may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular patient, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the Claimed compositions.

The precise time of administration and/or amount of the composition that will yield the most effective results in terms of efficacy of treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a particular compound, physiological condition of the patient (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), route of administration, etc. However, the above guidelines can be used as the basis for fine-tuning the treatment, e.g., determining the optimum time and/or amount of administration, which will require no more than routine experimentation consisting of monitoring the patient and adjusting the dosage and/or timing

The compounds of the present invention can be administered alone, in combination with other compounds of the present invention, or with other pharmaceutically active compounds or agents. The other pharmaceutically active compounds/agents can be intended to treat the same disease or condition as the compounds of the present invention or a different disease or condition. If the patient is to receive or is receiving multiple pharmaceutically active compounds or agents, the compounds can be administered simultaneously, or sequentially.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, may be used in combination with one or more additional pharmaceutically active compounds/agents. One or more additional pharmaceutically active compounds or agents may be administered separately, as part of a multiple dose regimen, from the compound of Formula I (e.g., sequentially, e.g., on different overlapping schedules with the administration of one or more compounds of Formula I (including any subgenera or specific compounds thereof). In other Claims, the one or more additional compounds/agents may be part of a single dosage form, mixed together with the compound of Formula I in a single composition. In still another Claim, the one or more additional compounds/agents can be given as a separate dose that is administered at about the same time that one or more compounds of Formula I are administered (e.g., simultaneously with the administration of one or more compounds of Formula I (including any subgenera or specific compounds thereof). Both the compound of Formula I and the one or more additional compounds/agents can be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.

In a particular claim, the additional pharmaceutically active compound/agent is a compound or agent that can be used to treat a cancer. For example, the additional pharmaceutically active compound/agent can be selected from antineoplastic agents, anti-angiogenic agents, chemotherapeutic agents, and peptidal cancer therapy agents. In another Claim, the antineoplastic agents are selected from antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, kinase inhibitors, proteasome inhibitors, and combinations thereof. It is noted that the additional pharmaceutically active compound/agent may be a traditional small organic chemical molecule or can be a macromolecule such as a protein, antibody, peptibody, DNA, RNA or a fragment of such macromolecules.

Examples of additional pharmaceutically active compounds/agents that can be used in the treatment of cancers and that can be used in combination with one or more compounds of the present invention include: acemannan; aclarubicin; aldesleukin; alitretinoin; amifostine; amrubicin; amsacrine; anagrelide; arglabin; arsenic trioxide; BAM 002 (Novelos); bicalutamide; broxuridine; celmoleukin; cetrorelix; cladribine; clotrimazole; cytarabine; DA 3030 (Dong-A); daclizumab; denileukin diftitox; deslorelin; dilazep; docosanol; doxercalciferol; doxifluridine; bromocriptine; cytarabine; HIT diclofenac; interferon alfa; tretinoin; edelfosine; edrecolomab; eflomithine; emitefur; epirubicin; epoetin beta; etoposide phosphate; exisulind; fadrozole; finasteride; fludarabine phosphate; formestane; fotemustine; gallium nitrate; gemtuzumab zogamicin; gimeracil/oteracil/tegafur combination; glycopine; goserelin; heptaplatin; human chorionic gonadotropin; human fetal alpha fetoprotein; ibandronic acid; interferon alfa; interferon alfa natural; interferon alfa-2; interferon alfa-2a; interferon alfa-2b; interferon alfa-N1; interferon alfa-n3; interferon alfacon-1; interferon alpha natural; interferon beta; interferon beta-1a; interferon beta-1b; interferon gamma natural; interferon gamma-1a; interferon gamma-1b; interleukin-1 beta; iobenguane; irsogladine; lanreotide; LC 9018 (Yakult); leflunomide; lenograstim; lentinan sulfate; letrozole; leukocyte alpha interferon; leuprorelin; levamisole+fluorouracil; liarozole; lobaplatin; lonidamine; lovastatin; masoprocol; melarsoprol; metoclopramide; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitoxantrone; molgramostim; nafarelin; naloxone+pentazocine; nartograstim; nedaplatin; nilutamide; noscapine; novel erythropoiesis stimulating protein; NSC 631570 octreotide; oprelvekin; osaterone; paclitaxel; pamidronic acid; peginterferon alfa-2b; 243rimethyl polysulfate sodium; pentostatin; picibanil; pirarubicin; rabbit antithymocyte polyclonal antibody; polyethylene glycol interferon alfa-2a; porfimer sodium; raltitrexed; rasburicase; rhenium Re 186 etidronate; RII retinamide; romurtide; samarium (153 Sm) lexidronam; sargramostim; sizofuran; sobuzoxane; sonermin; strontium-89 chloride; suramin; tasonermin; tazarotene; tegafur; temoporfin; teniposide; tetrachlorodecaoxide; thymalfasin; thyrotropin alfa; toremifene; tositumomab-iodine 131; treosulfan; tretinoin; trilostane; trimetrexate; triptorelin; trametinib; tumor necrosis factor alpha natural; ubenimex; bladder cancer vaccine; Maruyama vaccine; melanoma lysate vaccine; valrubicin; venetoclax; verteporfin; virulizin; zinostatin stimalamer; abarelix; AE 941 (Aetema); ambamustine; antisense oligonucleotide; bcl-2 (Genta); APC 8015 (Dendreon); dexaminoglutethimide; diaziquone; EL 532 (Elan); EM 800 (Endorecherche); eniluracil; etanidazole; fenretinide; galocitabine; gastrin 17 immunogen; HLA-B7 gene therapy (Vical); granulocyte macrophage colony stimulating factor; histamine dihydrochloride; ibritumomab tiuxetan; ilomastat; IM 862 (Cytran); interleukin-2; iproxifene; LDI 200 (Milkhaus); leridistim; lintuzumab; CA 125 monoclonal antibody (Mab) (Biomira); cancer Mab (Japan Pharmaceutical Development); HER-2 and Fc Mab (Medarex); idiotypic 105AD7 Mab (CRC Technology); idiotypic CEA Mab (Trilex); LYM-1-iodine 131 Mab (Techniclone); polymorphic epithelial mucin-yttrium 90 Mab (Antisoma); marimastat; menogaril; mitumomab; motexafin gadolinium; MX 6 (Galderma); nolatrexed; P 30 protein; pegvisomant; porfiromycin; prinomastat; RL 0903 (Shire); rubitecan; satraplatin; sodium phenylacetate; sparfosic acid; SRL 172 (SR Pharma); SU 5416 (SUGEN); TA 077 (Tanabe); tetrathiomolybdate; thaliblastine; thrombopoietin; tin ethyl etiopurpurin; tirapazamine; cancer vaccine (Biomira); melanoma vaccine; melanoma oncolysate vaccine; viral melanoma cell lysates vaccine; valspodarl; fluorouracil; 5-fluorouracil; 244rimethyla; imatinib; altretamine; cladibrine; cyclophosphamine; decarazine; irinotecan; mitosmycin; mitoxane; topotecan; vinorelbine; 244rimethyla; mithram; imiquimod; alemtuzmab; exemestane; bevacizumab; cetuximab; azacitidine; clofarabine; decitabine; desatinib; dexrazoxane; docetaxel; epirubicin; oxaliplatin; erlotinib; raloxifene; fulvestrant; letrozole; gefitinib; gemtuzumab; trastuzumab; gefitinib; ixabepilone; lapatinib; lenalidomide; aminolevulinic acid; temozolomide; nelarabine; sorafenib; nilotinib; pegaspargase; pemetrexed; rituximab; dasatinib; thalidomide; bexarotene; temsirolimus; bortezomib; 244rimethylam; oprozomib; vorinostat; capecitabine; zoledronic acid; anastrozole; sunitinib; aprepitant and nelarabine, or a pharmaceutically acceptable salt thereof.

Additional pharmaceutically active compounds/agents that can be used in the treatment of cancers and that can be used in combination with one or more compound of the present invention include: epoetin alfa; darbepoetin alfa; panitumumab; pegfilgrastim; palifermin; filgrastim; denosumab; ancestim; AMG 102; AMG 386; AMG 479; AMG 655; AMG 745; AMG 951; and AMG 706, or a pharmaceutically acceptable salt thereof.

In certain claims, a composition provided herein is conjointly administered with a chemotherapeutic agent. Suitable chemotherapeutic agents may include, natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, doxorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine), antiplatelet agents, antiproliferative/antimitotic alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogs, melphalan, and chlorambucil), ethylenimines and methylmelamines (e.g., hexaamethylmelaamine and thiotepa), CDK inhibitors (e.g., seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs, and streptozocin), trazenes-dacarbazinine (DTIC), antiproliferative/antimitotic antimetabolites such as folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoyl anilide hydroamic acid, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), mTor inhibitors (e.g., temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP(Eg5) inhibitors (e.g., Array 520), DNA binding agents (e.g., Zalypsis), PI3K delta inhibitor (e.g., GS-1101 and TGR-1202), PI3K delta and gamma inhibitor (e.g., CAL-130), multi-kinase inhibitor (e.g., TG02 and sorafenib), hormones (e.g., estrogen) and hormone agonists such as leutinizing hormone releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide and triptorelin), BAFF-neutralizing antibody (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNTO328), telomerase inhibitors (e.g., GRN 163L), aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CS1 (e.g., elotuzumab), inhibitors of KRAS including covalent inhibitors of KRAS G12C, MEK inhibitor, including trametinib, HSP90 inhibitors (e.g., 17 AAG and KOS 953), PI3K/Akt inhibitors (e.g., perifosine), Akt inhibitor (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zamestra™), anti-CD138 (e.g., BT062), Torc1/2 specific kinase inhibitor (e.g., INK128), kinase inhibitor (e.g., GS-1101), ER/UPR targeting agent (e.g., MKC-3946), cFMS inhibitor (e.g., ARRY-382), JAK1/2 inhibitor (e.g., CYT387), PARP inhibitor (e.g., olaparib and veliparib (ABT-888)), BCL-2 antagonist. Other chemotherapeutic agents may include mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, navelbine, sorafenib, or any analog or derivative variant of the foregoing.

The compounds of the present invention may also be used in combination with radiation therapy, hormone therapy, surgery and immunotherapy, which therapies are well known to those skilled in the art.

In certain claims, a pharmaceutical composition provided herein is conjointly administered with a steroid. Suitable steroids may include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts and/or derivatives thereof. In a particular Claim, the compounds of the present invention can also be used in combination with additional pharmaceutically active agents that treat nausea. Examples of agents that can be used to treat nausea include: dronabinol; granisetron; metoclopramide; ondansetron; and prochlorperazine; or a pharmaceutically acceptable salt thereof.

As one aspect of the present invention contemplates the treatment of the disease/conditions with a combination of pharmaceutically active compounds that may be administered separately, the invention further relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of the present invention, and a second pharmaceutical compound. The kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes, and bags. In some Claims, the kit comprises directions for the use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing health care professional.

The compounds of the present invention can be administered as pharmaceutically acceptable salts, esters, amides or prodrugs. The term “salts” refers to inorganic and organic salts of compounds of the present invention. The salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting a purified compound in its free base or acid form with a suitable organic or inorganic base or acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitiate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. The salts may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, 247rimethylamine, ethylamine, and the like. See, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J Pharm Sci, 66: 1-19 (1977).

The term “prodrug” means compounds that are transformed in vivo to yield a compound of the present invention. The transformation may occur by various mechanisms, such as through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

To illustrate, if the compound of the invention contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C₁-C₈ alkyl, (C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)aminomethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl and piperidino-, pyrrolidino- or morpholino(C₂₋₃)alkyl.

Similarly, if a compound of the present invention comprises an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl, N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkanoyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, —P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

The compounds of the present invention may contain asymmetric or chiral centers, and therefore, exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention contemplates all geometric and positional isomers. For example, if the compound contains a double bond, both the cis and trans forms (designated as Z and E, respectively), as well as mixtures, are contemplated.

Mixture of stereoisomers, such as diastereomeric mixtures, can be separated into their individual stereochemical components on the basis of their physical chemical differences by known methods such as chromatography and/or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., an alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.

The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water (hydrate), ethanol, and the like. The present invention contemplates and encompasses both the solvated and unsolvated forms.

It is also possible that compounds of the present invention may exist in different tautomeric forms. All tautomers of compounds of the present invention are contemplated. Those skilled in the art will recognize that the compound names and structures contained herein may be based on a particular tautomer of a compound. While the name or structure for only a particular tautomer may be used, it is intended that all tautomers are encompassed by the present invention, unless stated otherwise.

It is also intended that the present invention encompass compounds that are synthesized in vitro using laboratory techniques, such as those well known to synthetic chemists; or synthesized using in vivo techniques, such as through metabolism, fermentation, digestion, and the like. It is also contemplated that the compounds of the present invention may be synthesized using a combination of in vitro and in vivo techniques.

The compounds of the present invention may exist in various solid states including crystalline states and as an amorphous state. The different crystalline states, also called polymorphs, and the amorphous states of the present compounds are contemplated as part of this invention.

EXAMPLES

The examples presented below illustrate specific Claims of the present invention. These examples are meant to be representative and are not intended to limit the scope of the Claims in any manner.

The following abbreviations may be used herein:

-   ˜ about -   Ac acetate -   Ac₂O acetic anhydride -   AcOH acetic acid -   Al₂O₃ aluminum oxide -   br broad -   Boc tert-butyloxycarbonyl -   B(OiPr)₃ triisopropyl borate -   B(Oallyl)₃ triallyl borate -   B(OCH₂CF₃)₃ tris(2,2,2-trifluoroethyl) borate -   B(On-Bu)₃ tri-n-butyl borate -   Calcd calculated -   CO₂ carbon dioxide -   CSA 10-camphorsulfonic acid -   d day or doublet -   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene -   DCE dichloroethane -   DCM dichloromethane -   DEA diethylamine -   Dess-Martin periodinane     1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one -   DIPEA or DIEA diisopropylethylamine -   DMA N,N-dimethylacetamide -   DMF N,N-dimethylformamide -   DMSO dimethyl sulfoxide -   EDC N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide -   ee or e.e. enantiomeric excess -   ELISA enzyme-linked immunosorbent assay -   eq or equiv equivalent -   ESI or ES electrospray ionization -   Et ethyl -   Et₂O diethyl ether -   EtOAc ethyl acetate -   Et₃N triethylamine -   EtOH ethyl alcohol -   EtI ethyl iodide -   g gram(s) -   GC gas chromatography -   h hour(s) -   H₂ hydrogen gas -   HCl hydrochloric acid -   ¹H NMR proton nuclear magnetic resonance spectroscopy -   HATU     1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium     3-oxid hexafluorophosphate -   H₂O water -   HPLC high performance liquid chromatography -   H₂SO₄ sulfuric acid -   Hz Hertz -   IP intraperitoneal -   IPA isopropyl alcohol -   K₂CO₃ potassium carbonate -   KF Karl Fischer titration -   KHMDS potassium hexamethyldisilazide -   KOAc potassium acetate -   KOH potassium hydroxide -   K₃PO₄ potassium phosphate -   KOtBu potassium tert-butoxide -   L liter -   LAH lithium aluminium hydride -   LCMS, LC-MS, or LC/MS liquid chromatography mass spectrometry -   LHMDS lithium hexamethyldisilazide -   m multiplet -   mm millimeter -   M molar (mol/L) or mass -   Me methyl -   MeCN acetonitrile -   MeI iodomethane -   MeOH methyl alcohol -   MeTHF 2-methyltetrahydrofuran -   Me₃SI trimethylsulfonium iodide -   MeNH₂ methylamine -   Me₂NH dimethylamine -   mg milligram(s) -   MgSO₄ magnesium sulphate -   MHz megahertz -   μm micrometer -   μL microliter -   min minute(s) -   mL milliliter(s) -   mm millimeter(s) -   mol mole -   MS mass spectrometry -   MSA methanesulfonic acid -   MsCl methanesulfonyl chloride -   MTBE methyl tert-butyl ether -   m/z mass-to-charge ratio -   N Normality (Eq/L) -   N₂ nitrogen gas -   nBuLi n-butyllithium -   NaCl sodium chloride -   Na₂CO₃ sodium carbonate -   NaHCO₃ sodium bicarbonate -   NaH₂PO₄ sodium dihydrogen phosphate -   NaNO₂ sodium nitrite -   NaOH sodium hydroxide -   NaOtBu sodium tert-butoxide -   Na₂SO₄ sodium sulfate -   Na₂S₂O₃ sodium thiosulfate -   NH₃ ammonia, azane -   NH₄Cl ammonium chloride -   NH₄OH ammonium hydroxide -   NMP 1-methyl-2-pyrrolidinone -   NMR nuclear magnetic resonance spectroscopy -   OMe methoxy -   PO per oral -   +ve positive -   Ph phenyl -   PhMe toluene -   PMB p-methoxybenzyl -   POCl₃ phosphoryl chloride -   ppm parts per million -   prep preparative -   psi pounds per square inch -   q quartet -   QD once daily -   QNMR quantitative NMR -   Rac racemic -   RBF round-bottomed flask -   RT, rt, or r.t. room temperature -   s singlet -   sat. or satd or sat'd saturated -   SFC supercritical fluid chromatography -   SIMes 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene -   SiO₂ silica -   SOCl₂ thionyl chloride -   t triplet -   TBDPS tert-butyldiphenylsilyl -   TBS tert-butyldimethylsilyl -   TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl -   t-BuOH tert-butanol -   TFA triflouroacetic acid -   THF tetrahydrofuran -   Ti(OiPr)₄ titanium isopropoxide -   TLC thin layer chromatography -   TsOH toluene sulfonic acid -   UV ultraviolet -   v/v volume per volume -   wt % weight percent

It is noted that when a percent (%) is used with regard to a liquid, it is a percent by volume with respect to the solution. When used with a solid, it is the percent with regard to the solid composition.

General Synthetic Schemes

Unless otherwise stated, starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

The starting materials for the following synthetic methods can be found in the General Methods and General Synthesis for Intermediates. The synthesis of some of the starting materials and the intermediates are disclosed in U.S. Pat. No. 9,562,061 and PCT/US17/19336, respectively, herein incorporated by reference in their entireties for all purposes. These synthetic methods are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these methods can be made and will be suggested to one skilled in the art having referred to this disclosure. The starting materials and the intermediates, and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about −78° C. to about 150° C., more preferably from about 0° C. to about 125° C. and most preferably at about room (or ambient) temperature, e.g., about 22° C.

IUPAC names were generated using either ACD/Name v2015 or ChemBioDraw Ultra 12.

General Method 1: Enone Synthesis

General Method 2: Enone Synthesis

General Method 3: Conversion of Enone to Aldehyde Via Epoxide

General Method 4: Conversion of Ketone to Aldehyde Via Epoxide

General Method 5: Conversion of Ketone to Aldehyde Via Dithiane

General Method 6: Conversion of Ketone to Amino Alcohol Via Epoxide

General Method 7: Conversion of Enone to Amino Ether

General Methods 8: Reductive Amination with NaBH(OAc)₃

General Methods 9: Reductive Amination with NaBH₄, Ti(OiPr)₄, and Amine Salt

General Methods 10: Reductive Amination with NaBH(OAc)₃ and Amine Salt

General Methods 11: Reductive Amination with NaBH(OAc)₃, Ti(OiPr)₄, and Amine Salt

General Methods 12: Reductive Amination with NaBH(OAc)₃ and AcOH

General Methods 13: Reductive Amination with NaBH₃CN and AcOH

Example 1 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide General Method 3 (Steps 1-3), General Method 7 (Step 1), General Method 8 (Step 4)

Step 1: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2′-oxiran]-15′-one 13′,13′-dioxide

A 250 mL 3-neck, equipped with a thermocouple, nitrogen inlet and septum, was charged with (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′ [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (10.05 g, 15.48 mmol) and trimethylsulfonium iodide (4.79 g, 23.47 mmol). Dimethyl sulfoxide (80 mL) and tetrahydrofuran (20 mL) were added and the reaction was cooled to 5° C. using an ice-water bath. The reaction was treated with 1 M potassium t-butoxide in THF (39.0 mL, 39.0 mmol) via syringe over a period of 20 min. The reaction was quenched with glacial acetic acid (2.20 mL, 38.1 mmol) and stirred for 1 min. The mixture was poured into isopropyl acetate (200 mL) and washed with water (200 mL). The aqueous layer was extracted with isopropyl acetate (100 mL) and the combined organic layers were washed with water (3×200 mL), brine (60 mL) and dried over Na₂SO₄. The solution was filtered and the filtrate was concentrated under reduced pressure. The residue was azeotrope with DCM (2×200 mL) then dissolved in DCM (40 mL). Heptane (400 mL) was added dropwise over a period of 1 h and the mixture was then stirred for 30 min. The solids were filtered and dried with nitrogen purge on the frit for 3 h to give 8.60 g of (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-oxiran]-15′-one 13′,13′-dioxide as a white solid. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 8.08 (s, 1H), 7.72 (d, J=8.41 Hz, 1H), 7.22 (d, J=0.98 Hz, 1H), 7.19 (dd, J=8.41, 2.35 Hz, 1H), 7.09 (d, J=2.15 Hz, 1H), 6.83-6.95 (m, 2H), 5.73-5.91 (m, 1H), 5.60 (d, J=15.26 Hz, 1H), 4.20 (q, J=7.24 Hz, 1H), 4.01-4.14 (m, 2H), 3.92 (dd, J=15.45, 4.50 Hz, 1H), 3.73 (br d, J=14.28 Hz, 1H), 3.20 (d, J=14.28 Hz, 1H), 2.96 (dd, J=15.55, 6.55 Hz, 1H), 2.65-2.85 (m, 2H), 2.47 (d, J=5.48 Hz, 1H), 2.25-2.43 (m, 2H), 1.73-2.08 (m, 9H), 1.60-1.72 (m, 1H), 1.33-1.44 (m, 4H), 1.03 (br d, J=5.87 Hz, 3H).

Step 2: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

A 1 L 3-neck, equipped with a thermocouple, nitrogen adapter and septum, was charged with (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-oxiran]-15′-one 13′,13′-dioxide (10.22 g, 16.72 mmol) and 2-methyltetrahydrofuran (300 mL). Triethyl borate (50 mL, 291 mmol) was added via syringe and the reaction was placed on a heat block preheated to 65° C. After 12 h the reaction was cooled to room temperature overnight. The reaction mixture was quenched with saturated NaHCO₃ (100 mL) and stirred for 10 min. The aqueous layer was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine (50 mL), dried over Na₂SO₄ and filtered. The filtrate was evaporated onto silica gel and purified by flash chromatography (Isco (330 gram)) eluting with 0.3% AcOH in EtOAc:0.3% AcOH in heptane (0:1→1:1) to afford 6.27 g of (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide. MS (ESI, +ve ion) m/z 657.3 (M+1)⁺.

Step 3: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo [14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide

A 250 mL 3-neck, equipped with a thermocouple, nitrogen adapter and septum, was charged with the starting (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (6.27 g, 7.54 mmol), DCM (50 mL) and dimethyl sulfoxide (20 mL). The solution was cooled (0° C.) in an ice bath, and N,N-diisopropylethylamine was added (6.6 mL, 37.8 mmol) followed by sulfur trioxide pyridine complex (3.02 g, 18.97 mmol), portion wise over 15 min. The ice bath was removed and allowed to warm to room temperature for 2 h. The reaction mixture was poured into isopropyl acetate (200 mL) and the solution was washed with water (200 mL). The aqueous layer was extracted with EtOAc (1×100 mL) and the combined organic layers were washed with 50% saturated NH₄Cl (2×100 mL), water (50 mL), brine (50 mL) and dried over Na₂SO₄. The solution was filtered and the filtrate was concentrated under reduced pressure to give a light-yellow solid. The solid was dissolved in EtOAc, evaporated onto silica gel and purified by flash chromatography (Isco (220 gram)) eluting with 0.3% AcOH in EtOAc:0.3% AcOH in heptane (0:1-1:1) to give 4.44 g of (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide as a white solid. MS (ESI, +ve ion) m/z 655.3 (M+1)⁺.

Step 4: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Preparation of amine free base: To a room temperature suspension of (S)-octahydropiperazino[2,1-c]morpholine dihydrochloride (7.04 g, 32.7 mmol; Synthonix, Wake Forest, N.C.) in DCM (100 mL) was added sodium methoxide (25 wt % solution in methanol, 15 mL, 65.6 mmol) and the reaction was stirred for 2 h. The solvent was removed under reduced pressure and the residue was stirred over EtOAc (100 mL) for 1 h. The solution was filtered and the filtrate was concentrated under reduced pressure to give (S)-octahydropyrazino[2,1-c][1,4]oxazine (4.33 g) as a light-yellow oil. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 3.70-3.82 (m, 1H), 3.61-3.67 (m, 1H), 3.52-3.60 (m, 1H), 3.15 (t, J=10.47 Hz, 1H), 2.79-2.93 (m, 2H), 2.60-2.71 (m, 2H), 2.55 (br d, J=11.54 Hz, 1H), 2.27-2.39 (m, 2H), 2.05-2.21 (m, 2H).

To a room temperature solution of (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (4.44 g, 6.51 mmol) in 1,2-dichloroethane (40 mL) was added a solution of (S)-octahydropyrazino[2,1-c][1,4]oxazine (2.91 g, 18.01 mmol) in 1,2-dichloroethane (5 mL) and the reaction was stirred for 2 h. To the reaction was added sodium triacetoxyborohydride (0.350 g, 1.651 mmol) was added as a solid. Additional sodium triacetoxyborohydride (0.350 g, 1.651 mmol) was added until the reaction was complete. The reaction was quenched with saturated NH₄Cl (40 mL) and the layers were separated. The aqueous layer was extracted with DCM (2×) and the combined organic layers were washed with 1 M KH₂PO₄ (40 mL). The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure and stored in the freezer. The residual material was dissolved in DCM, evaporated onto silica gel, and purified by flash chromatography (Isco (330 gram)) eluting with EtOAc:heptane:MeOH:DCM (0:1:0:0→3:2:0:0→0:0:1:49→0:0:3:47) to give 3.63 g (70%) of an off-white solid. The material was stirred over MeOH (15 mL) for 1 h. To the thick slurry was added MeOH (30 mL) to maintain good stirring. After another 1 h the solvent was removed under reduced pressure and the residue was dried in vacuo. The solid was dried under nitrogen purge/vacuum for 24 h to give 3.10 g of (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide as a white solid. MS (ESI, +ve ion) m/z 781.3 (M+1)⁺. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 7.72 (d, J=8.41 Hz, 1H), 7.23 (s, 1H), 7.17 (dd, J=8.41, 1.96 Hz, 1H), 7.09 (d, J=1.96 Hz, 1H), 6.89 (s, 2H), 5.58-5.75 (m, 1H), 5.43 (br d, J=15.85 Hz, 1H), 4.15 (q, J=6.85 Hz, 1H), 4.07 (s, 2H), 4.01 (br d, J=15.45 Hz, 1H), 3.74-3.82 (m, 1H), 3.71 (br d, J=14.08 Hz, 1H), 3.54-3.66 (m, 3H), 3.43-3.52 (m, 1H), 3.27 (d, J=14.28 Hz, 1H), 3.17 (br t, J=10.37 Hz, 1H), 2.89-3.03 (m, 2H), 2.72-2.85 (m, 2H), 2.58-2.71 (m, 2H), 2.54 (m, 2H), 2.48 (br d, J=14.28 Hz, 1H), 2.20-2.40 (m, 5H), 2.03-2.20 (m, 4H), 1.65-2.00 (m, 6H), 1.54-1.64 (m, 2H), 1.41 (d, J=7.24 Hz, 3H), 1.30-1.38 (m, 4H), 1.01 (br d, J=5.67 Hz, 3H).

Example 2 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a room temperature solution of (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (0.050 g, 0.076 mmol) in 1,2-dichloroethane (1 mL) was added 1-(oxetan-3-yl)piperazine (0.100 mL, 0.823 mmol, Astatech, Inc., Bristol Pa.) via syringe and the reaction was stirred for 1 h. To the reaction was added sodium triacetoxyborohydride (0.050 g, 0.236 mmol) as a solid and the reaction was stirred overnight. The reaction was quenched with pH 7 buffer and the layers were separated. The aqueous layer was extracted with DCM (3×) and the combined organic layers were concentrated under reduced pressure. The residue was dissolved in MeOH and purified by reverse-phase HPLC (Gilson; Gemini-NX 10 m C18 110 Å AXIA, 100×50 mm column) eluting with 0.1% TFA-H₂O:0.1% TFA CH₃CN (7:3→5:95). The fractions containing the desired product were combined, treated with pH 7 buffer (1 M KH₂PO₄/1 M K₂HPO₄; 5 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were washed with brine and dried over Na₂SO₄. The solution was filtered and concentrated under reduced pressure to give (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (47 mg, 79%) as a white crystalline solid. MS (ESI, +ve ion) m/z 781.2 (M+1)⁺. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 8.07 (br s, 1H), 7.71 (d, J=8.41 Hz, 1H), 7.23 (s, 1H), 7.17 (dd, J=8.51, 2.25 Hz, 1H), 7.08 (d, J=2.15 Hz, 1H), 6.82-6.93 (m, 2H), 5.61-5.78 (m, 1H), 5.45 (br d, J=15.85 Hz, 1H), 4.56-4.66 (m, 2H), 4.44-4.54 (m, 2H), 4.15 (br d, J=7.04 Hz, 1H), 4.03-4.10 (m, 2H), 3.99 (br d, J=14.67 Hz, 1H), 3.70 (br d, J=14.28 Hz, 1H), 3.61 (quin, J=7.24 Hz, 1H), 3.35-3.52 (m, 2H), 3.26 (d, J=14.28 Hz, 1H), 2.95 (br dd, J=14.87, 9.98 Hz, 1H), 2.72-2.85 (m, 2H), 2.59-2.71 (m, 2H), 2.46-2.57 (m, 4H), 2.24-2.41 (m, 4H), 2.02-2.19 (m, 4H), 1.78-1.98 (m, 3H), 1.70 (br s, 1H), 1.57 (br d, J=6.26 Hz, 4H), 1.29-1.45 (m, 7H), 1.00 (br d, J=5.09 Hz, 3H).

Example 3 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8, 16,18,24]tetraen]-15′-one 13′,13′-dioxide General Method 5 (Steps 1-3)

Step 1: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-(1,3-DITHIAN-2-YL)-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE AND (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-(1,3-DITHIAN-2-YL)-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE

To a 250 mL round-bottomed flask was added 1,3-dithiane (4.79 g, 39.8 mmol) and THF (100 mL). The mixture was cooled to −78° C. and n-butyllithium (1.6 M solution in hexane, 22.5 mL, 36.1 mmol) was added over 8 min. The solution was stirred in the −78° C. bath for 30 min. In a separate 100 mL flask was added (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide and THF (5 mL). To this was added lanthanum(III) chloride bis(lithium chloride) complex solution (0.6 M in THF, 60.1 mL, 36.1 mmol) and this was stirred for 5 min at room temperature. The solution was then cooled to −78° C. and added via cannula to the dithiane solution. After 2.5 h at −78° C., the solution was treated with sat NH₄Cl and water. The pH of the solution was adjusted to pH=4 with aqueous 10% citric acid and aqueous NaHCO₃. The solution was extracted with EtOAc and the combined extracts were filtered through Celite. The filtrate was washed with water and brine and then dried (Na₂SO₄) and concentrated to afford a mixture of (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide and (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide as a brown oil which was carried on directly to next step. MS (ESI, +ve ion) m/z 717.5 (M+H)⁺.

Step 2: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-(1,3-DITHIAN-2-YL)-7′-METHOXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE AND (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-(1,3-DITHIAN-2-YL)-7′-METHOXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE

To a resealable vial was added the mixture of (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide and (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (6.81 g, 9.49 mmol) and THF (100 mL). The mixture was cooled to 0° C. and potassium bis(trimethylsilyl)amide (1 M in THF, 38.0 mL, 38.0 mmol) was added over 10 min. The solution was stirred at 0° C. for 5 min and then iodomethane (2.36 mL, 38.0 mmol) was added over 3 min. After 2.5 h at 0° C., the solution was poured into saturated NH₄Cl and the pH was adjusted to 4 with 1 M citric acid. The solution was extracted with EtOAc and the combined extracts were washed with brine, dried (Na₂SO₄) and concentrated onto silica. Purification by silica gel chromatography (0% to 35% EtOAc/heptane, both with 0.3% AcOH v/v, 330 g Redi-Sep Gold column) afforded: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (1.66 g, 2.27 mmol, 24% yield). MS (ESI, +ve ion) m/z 731.5 (M+H)⁺ and (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (4.69 g, 6.41 mmol, 68% yield). MS (ESI, +ve ion) m/z 731.5 (M+H)⁺.

Step 3: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide

To a 250 mL round-bottomed flask equipped with a reflux condenser was added (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (1.63 g, 2.23 mmol), acetonitrile (40 mL) and water (10 mL). The mixture was heated to 50° C. and calcium carbonate (1.12 g, 11.1 mmol) and iodomethane (1.38 mL, 22.3 mmol) were added. After 23 h at 50° C., the solution was poured into sat NH₄Cl and water and then extracted with EtOAc. The combined extracts were washed with brine and then dried (Na₂SO₄) and concentrated onto silica. Purification by silica gel chromatography (0% to 40% EtOAc/heptane (both with 0.3% AcOH), Silicycle HP 120 g column) afforded (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (1.34 g, 2.09 mmol, 94% yield) as a white solid. MS (ESI, +ve ion) m/z 641.3 (M+H)⁺.

Step 4: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-METHOXY-11′,12′-DIMETHYL-7′-((4-(3-OXETANYL)-1-PIPERAZINYL)METHYL)-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE

To a resealable vial was added (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (0.135 g, 0.211 mmol), 1,2-dichloroethane (2.0 mL) and 1-(oxetan-3-yl)piperazine (0.090 g, 0.632 mmol, AstaTech, Inc.). The solution was stirred at room temperature for 1 h. To this solution was added sodium triacetoxyborohydride (0.011 g, 0.053 mmol). After stirring overnight at room temperature, additional portions of sodium triacetoxyborohydride (0.011 g, 0.053 mmol) were added until the reaction was complete. The reaction was carefully quenched with MeOH stirred for 1 h and then filtered for Prep-HPLC purification. The solution was purified by prep-HPLC (Column: Phenomenex Luna 5μ C18, 100 Å, 150×20 mm; Solvent: A=water (0.1% TFA), B=(R) (0.1% TFA), 30 mL/min, 30% B to 100% B over 18 min then 2 min at 100% B) and the fractions containing product were treated with aqueous pH 7 buffer (KH₂PO₄/K₂HPO₄ based) and extracted with EtOAc. The combined extracts were washed with brine, and then dried (Na₂SO₄), filtered and concentrated to afford (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide as a white solid (0.101 g, 0.132 mmol, 63% yield). ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 7.72 (d, J=9.8 Hz, 1H), 7.25 (br s, 1H), 7.16 (br d, J=8.6 Hz, 1H), 7.09 (s, 1H), 6.89 (s, 2H), 5.62 (br s, 1H), 5.37 (br d, J=14.9 Hz, 1H), 4.56-4.66 (m, 2H), 4.52 (br t, J=5.9 Hz, 2H), 4.12 (br d, J=6.5 Hz, 1H), 4.06 (s, 2H), 3.98 (br d, J=14.9 Hz, 1H), 3.70 (br d, J=14.1 Hz, 1H), 3.40-3.52 (m, 1H), 3.36 (s, 3H), 3.19-3.30 (m, 1H), 2.90-3.03 (m, 1H), 2.64-2.85 (m, 4H), 2.45-2.63 (m, 5H), 2.26-2.41 (m, 4H), 2.15-2.25 (m, 1H), 2.02-2.15 (m, 3H), 1.78-1.99 (m, 4H), 1.66-1.76 (m, 1H), 1.49-1.64 (m, 2H), 1.40 (br d, J=7.2 Hz, 4H), 1.01 (br d, J=5.7 Hz, 3H). MS (ESI, +ve ion) m/z 767.3 (M+H)⁺.

Example 4 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-((9AS)-HEXAHYDROPYRAZINO[2,1-C][1,4]OXAZIN-8(1H)-YLMETHYL)-7′-METHOXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE General Method 9

To a 100 mL 3-neck flask was added (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (0.486 g, 0.758 mmol), DCM (20 mL) and ethanol (8.0 mL). To this solution was added (9aS)-octahydropiperazino[2,1-c]morpholine dihydrochloride (1.96 g, 9.10 mmol) followed by N,N-diisopropylethylamine (4.0 mL, 22.7 mmol). To the solution was added titanium(iv) isopropoxide (2.24 mL, 7.58 mmol). The solution was stirred at room temperature for 17 h. To this solution was added sodium borohydride (0.143 g, 3.79 mmol) in 3 portions. The reaction mixture was stirred at room temperature. After 18 h, additional sodium borohydride (35 mg) was added and stirring was continued at room temperature for an additional 24 h. The reaction was carefully quenched with sat. NH₄Cl and then diluted with aqueous pH 7 buffer (KH₂PO₄/K₂HPO₄ based), filtered through Celite, and extracted with EtOAc. The combined extracts were washed with brine, dried (Na₂SO₄), filtered and concentrated to afford a white solid. The solid was purified by prep-HPLC (Column: Phenomenex Gemini C18 110 Å, 100×50 mm; Solvent: A=water (0.1% TFA), B=(R) (0.1% TFA), 100 mL/min, 10% B to 100% B over 11 min then 2 min at 100% B) and the fractions containing product were treated with aqueous pH 7 buffer (KH₂PO₄/K₂HPO₄ based), concentrated to remove the acetonitrile, and extracted with EtOAc. The combined extracts were washed with brine, dried (Na₂SO₄), filtered and concentrated to afford (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide as a white solid (0.478 g, 0.622 mmol, 82% yield). ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 7.72 (d, J=8.6 Hz, 1H), 7.26 (s, 1H), 7.17 (dd, J=8.5, 2.2 Hz, 1H), 7.09 (d, J=2.3 Hz, 1H), 6.85-6.93 (m, 2H), 5.57-5.68 (m, 1H), 5.35 (s, 1H), 4.08-4.17 (m, 1H), 4.07 (s, 2H), 3.96-4.04 (m, 1H), 3.78 (br d, J=9.6 Hz, 1H), 3.70 (br d, J=14.3 Hz, 1H), 3.59 (br d, J=10.8 Hz, 2H), 3.35 (s, 3H), 3.25 (d, J=14.3 Hz, 1H), 3.17 (br s, 1H), 2.88-3.06 (m, 2H), 2.72-2.81 (m, 2H), 2.58-2.67 (m, 2H), 2.45-2.54 (m, 3H), 2.30-2.37 (m, 2H), 2.17-2.27 (m, 3H), 2.07-2.14 (m, 2H), 2.03-2.07 (m, 1H), 1.90-1.99 (m, 2H), 1.81-1.90 (m, 2H), 1.66-1.75 (m, 1H), 1.48-1.65 (m, 4H), 1.36-1.44 (m, 4H), 1.02 (d, J=6.1 Hz, 3H) MS (ESI, +ve ion) m/z 767.7 (M+H)⁺.

Example 5 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-METHOXY-11′,12′-DIMETHYL-7′-((4-(1-METHYLETHYL)-1-PIPERAZINYL)METHYL)-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE

To a resealable vial was added (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (0.135 g, 0.211 mmol), 1,2-dichloroethane (2 mL) and 1-isopropylpiperazine (0.090 mL, 0.632 mmol, Across Organics). The solution was stirred at room temperature for 1 h. To this solution was added sodium triacetoxyborohydride (0.011 g, 0.053 mmol). After 2 h at room temperature, additional 0.25 eq. portions of sodium triacetoxyborohydride were added (4 total) until the reaction was complete. The reaction mixture was carefully quenched with MeOH, stirred for 1 h, and then filtered for Prep-HPLC purification. The solution was purified by prep-HPLC (Column: Phenomenex Luna C18, 100 Å, 150×21.20 mm; Solvent: A=water (0.1% TFA), B=(R) (0.1% TFA), 30 mL/min, 30% B to 100% B over 18 min then 2 min at 100% B) and the fractions containing product were treated with aqueous pH 7 buffer (KH₂PO₄/K₂HPO₄ based) and extracted with EtOAc. The combined extracts were washed with brine, and then dried (Na₂SO₄), filtered and concentrated to afford (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(1-methylethyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide as a white solid (0.0855 g, 0.113 mmol, 54% yield). ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 7.76 (d, J=8.6 Hz, 1H), 7.30 (s, 1H), 7.20 (br d, J=8.4 Hz, 1H), 7.13 (s, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.92 (d, J=9.0 Hz, 1H), 5.63-5.74 (m, 1H), 5.49 (d, J=15.8 Hz, 1H), 4.10 (s, 2H), 3.96-4.05 (m, 2H), 3.74 (br d, J=14.3 Hz, 1H), 3.46 (s, 1H), 3.38-3.43 (m, 1H), 3.37 (s, 3H), 3.30 (br d, J=14.3 Hz, 1H), 2.96-3.04 (m, 2H), 2.85-2.94 (m, 2H), 2.77-2.84 (m, 2H), 2.54-2.68 (m, 3H), 2.36-2.43 (m, 1H), 2.23-2.35 (m, 2H), 2.14-2.23 (m, 2H), 2.06-2.14 (m, 2H), 1.83-2.03 (m, 4H), 1.50-1.76 (m, 4H), 1.35-1.47 (m, 10H), 1.05 (d, J=6.7 Hz, 3H). MS (ESI, +ve ion) m/z 753.2 (M+H)⁺.

Example 6 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-7′-((4-TERT-BUTYL-1-PIPERAZINYL)METHYL)-6-CHLORO-7′-ETHOXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE

To a resealable vial was added (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide, 0.035 g, 0.053 mmol), 1,2-dichloroethane (0.7 mL) and N-t-butylpiperazine (0.026 mL, 0.160 mmol, Oakwood Products, Inc.). The solution was stirred at room temperature for 30 min. To this solution was added sodium triacetoxyborohydride (2.83 mg, 0.013 mmol.). The reaction was stirred at room temperature. After 1 h, additional portions of sodium triacetoxyborohydride (2.83 mg, 0.013 mmol) were added every 1 h until the reaction was complete. The reaction was carefully quenched with MeOH, stirred for 30 min and then concentrated. Purification by silica gel chromatography (0% to 10% MeOH/CH₂Cl₂) afforded (1S,3′R,6′R,7′R,8′E,11′S,12′R)-7′-((4-tert-butyl-1-piperazinyl)methyl)-6-chloro-7′-ethoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide as a white solid (0.0284 g, 0.036 mmol, 68% yield). ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 7.73 (d, J=8.6 Hz, 1H), 7.31 (s, 1H), 7.16 (dd, J=8.5, 2.2 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 7.02 (br d, J=8.0 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 5.55-5.74 (m, 2H), 3.96-4.10 (m, 3H), 3.79 (br s, 1H), 3.69 (br d, J=14.5 Hz, 1H), 3.50-3.65 (m, 1H), 3.34-3.45 (m, 1H), 3.30 (d, J=14.3 Hz, 1H), 2.94-3.04 (m, 1H), 2.73-2.80 (m, 2H), 2.58-2.68 (m, 3H), 2.45-2.57 (m, 3H), 2.29-2.35 (m, 1H), 2.03-2.18 (m, 4H), 1.90-1.98 (m, 2H), 1.81-1.90 (m, 2H), 1.55-1.70 (m, 3H), 1.45-1.53 (m, 1H), 1.34-1.44 (m, 1H), 1.24-1.31 (m, 9H), 1.17-1.24 (m, 9H), 1.00 (d, J=6.8 Hz, 3H). MS (ESI, +ve ion) m/z 781.3 (M+H)⁺.

Example 7 (1S,3′R,6′R,7′S,11′S,12′R)-6-CHLORO-7′-((9AS)-HEXAHYDROPYRAZINO [2,1-C][1,4]OXAZIN-8(1H)-YLMETHYL)-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIEN]-15′-ONE 13′,13′-DIOXIDE General Method 6 (Steps 1-2)

Step 1: (1S,3′R,6′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,2″-oxiran]-15′-one 13′,13′-dioxide

To a stirred solution of (1S,3′R,6′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene]-7′,15′-dione 13′,13′-dioxide (100 mg, 0.167 mmol) and trimethylsulfoxonium iodide (38.6 mg, 0.175 mmol) in DMSO (1.5 mL) was added potassium hydroxide (33.0 mg, 0.501 mmol) at room temperature. The resulting mixture was stirred at room temperature for a period of 18 h. The mixture was poured into saturated ammonium chloride aqueous solution and extracted with EtOAc (2×). The combined organics were dried over anhydrous sodium sulfate. The residue was subjected to combi-flash column chromatography on a 12 g ISCO gold column eluting with 10% to 100% EtOAc/hexanes to give (1S,3′R,6′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,2″-oxiran]-15′-one 13′,13′-dioxide (72 mg, 0.117 mmol, 70% yield) as a mixture of diastereomers. MS (ESI, +ve ion) m/z 613.1 (M+H)⁺.

Step 2: (1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide

A mixture of (1S,3′R,6′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,2″-oxiran]-15′-one 13′,13′-dioxide (840 mg, 1.37 mmol), (S)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (1.47 g, 6.85 mmol), and triethylamine (3.00 mL, 21.6 mmol) in EtOH (6.0 mL) in a sealed microwave reaction vessel was subjected to microwave reaction condition (24 h, 90° C.). The crude mixture was directly loaded onto a silica gel precolumn (25 g) and subjected to combi-flash column chromatography on a 12 g ISCO gold column eluting with 0% to 20% MeOH/DCM to give an impure mixture of two epimeric beta-hydroxylamine products, which was subjected to separation by SFC (Column: MSA, Mobile Phase: 65:35 (A:B) isocratic, A: Liquid CO₂, B: methanol (20 mM NH₃), Flow Rate: 70 g/min, Column/Oven temp.: 40° C., Detection: UV at 240 nm). The epimer first eluting on both the reverse-phase prep-HPLC and the SFC column was collected and subjected to combi-flash column chromatography on a 12 g ISCO gold column eluting with 0 to 20% MeOH/DCM to give (1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide (340 mg, 0.45 mmol, 33% yield) as a white solid. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ 7.72 (d, J=8.61 Hz, 1H), 7.17 (dd, J=2.15, 8.41 Hz, 1H), 7.09 (d, J=2.15 Hz, 1H), 7.01 (s, 1H), 6.91-6.99 (m, 2H), 4.04-4.15 (m, 3H), 3.87 (br d, J=15.06 Hz, 1H), 3.78 (dd, J=2.93, 11.15 Hz, 1H), 3.69 (br d, J=14.28 Hz, 1H), 3.56-3.65 (m, 2H), 3.16-3.27 (m, 2H), 3.00 (br dd, J=8.71, 15.16 Hz, 1H), 2.87 (br d, J=9.98 Hz, 1H), 2.59-2.79 (m, 7H), 2.44-2.54 (m, 3H), 2.23-2.41 (m, 4H), 1.98-2.12 (m, 3H), 1.87-1.96 (m, 2H), 1.80-1.86 (m, 1H), 1.69-1.78 (m, 2H), 1.55 (br dd, J=9.29, 13.79 Hz, 3H), 1.20-1.44 (m, 9H), 0.98 (d, J=6.65 Hz, 3H). MS (ESI, +ve ion) m/z 755.3 (M+H)⁺.

Example 8 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-METHOXY-11′,12′-DIMETHYL-7′-(((3R)-3-METHYL-4-(1-METHYLETHYL)-1-PIPERAZINYL)METHYL)-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE

Step 1: (R)-TERT-BUTYL 4-ISOPROPYL-3-METHYLPIPERAZINE-1-CARBOXYLATE

A mixture of (R)-1-boc-3-methyl-piperazine (630 mg, 3.15 mmol) and acetone (3.0 mL, 40.9 mmol) in DCM (4.0 mL) was stirred for 10 min before sodium triacetoxyborohydride (1333 mg, 6.29 mmol) was added in one portion as a solid. The resulting mixture was stirred at room temperature for 2.5 days. MeOH (0.5 mL) was added to the reaction and the mixture was stirred for 5 min and then directly loaded onto a silica gel precolumn (25 g) and subjected to combi-flash column chromatography on a 24 g ISCO gold column eluting with 2% to 20% MeOH/DCM to give (R)-tert-butyl 4-isopropyl-3-methylpiperazine-1-carboxylate (0.72 g, 2.97 mmol, 94% yield) as a colorless oil. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ 3.54-3.90 (m, 2H), 3.25 (td, J=6.41, 13.01 Hz, 1H), 3.02 (br s, 1H), 2.64-2.84 (m, 2H), 2.52-2.63 (m, 1H), 2.19-2.34 (m, 1H), 1.43 (s, 9H), 1.10 (d, J=6.65 Hz, 3H), 1.04 (d, J=6.26 Hz, 3H), 0.90 (d, J=6.65 Hz, 3H). MS (ESI, +ve ion) m/z 243.2 (M+H)⁺.

Step 2: (R)-1-ISOPROPYL-2-METHYLPIPERAZINE BIS-TFA SALT

To a stirred solution of (R)-tert-butyl 4-isopropyl-3-methylpiperazine-1-carboxylate (670 mg, 2.76 mmol) in DCM (10 mL) was added trifluoroacetic acid (3.0 mL, 40 mmol) at room temperature. The resulting mixture was stirred at room temperature for 40 min. The volatiles were removed and the residue was subjected to high vacuum to give (R)-1-isopropyl-2-methylpiperazine bis-TFA salt as an off-white solid. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ 11.33-12.07 (m, 2H), 10.45-11.02 (m, 1H), 3.88-4.10 (m, 3H), 3.72-3.86 (m, 2H), 3.49-3.65 (m, 3H), 1.46 (dd, J=6.46, 12.91 Hz, 6H), 1.31 (d, J=6.65 Hz, 3H). MS (ESI, +ve ion) m/z 143.2 (M+H)⁺.

Step 3: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-Chloro-7′-methoxy-11′,12′-dimethyl-7′-(((3R)-3-methyl-4-(1-methylethyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a stirred mixture of (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (20 mg, 0.031 mmol) and (R)-1-isopropyl-2-methylpiperazine bis-TFA salt (76.2 mg, 0.206 mmol) in DCM (1.5 mL) was added N,N-diisopropylethylamine (0.50 mL, 2.9 mmol). The resulting mixture was stirred at room temperature for 10 min before sodium triacetoxyborohydride (26.4 mg, 0.125 mmol) was added in one portion as a solid. The resulting mixture was stirred at room temperature for 25 h. The reaction mixture was concentrated in vacuo and the residue was dissolved and taken up in MeOH and subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 10 μm column; Phenomenex, Torrance, Calif.; gradient elution of 35 to 90% MeCN in water, where both solvents contain 0.1% TFA, 15-min gradient in a 24 min method) to give, after lyophilization, (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-Chloro-7′-methoxy-11′,12′-dimethyl-7′-(((3R)-3-methyl-4-(1-methylethyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (17.6 mg, 0.020 mmol, 64% yield) as a TFA salt as a white solid. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ 8.08 (br s, 1H), 7.71 (d, J=8.61 Hz, 1H), 7.11-7.20 (m, 2H), 7.09 (d, J=1.76 Hz, 1H), 6.90 (s, 2H), 5.78-5.96 (m, 1H), 5.47 (br d, J=15.65 Hz, 1H), 4.13-4.26 (m, 1H), 4.07 (s, 2H), 3.82-3.99 (m, 2H), 3.58-3.77 (m, 2H), 3.20-3.51 (m, 9H), 2.92-3.04 (m, 1H), 2.74-2.82 (m, 3H), 2.51-2.62 (m, 2H), 2.02-2.18 (m, 6H), 1.85-1.97 (m, 3H), 1.72-1.79 (m, 1H), 1.55-1.68 (m, 2H), 1.35-1.45 (m, 10H), 1.24 (d, J=6.85 Hz, 3H), 1.02 (d, J=6.65 Hz, 3H). MS (ESI, +ve ion) m/z 767.2 (M+H)⁺.

Example 9 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-ETHOXY-11′,12′-DIMETHYL-7′-(((3R)-3-METHYL-4-(1-METHYLETHYL)-1-PIPERAZINYL)METHYL)-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE General Method 10

To an 1-dram vial was placed (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (12 mg, 0.018 mmol) followed by a solution of (R)-1-isopropyl-2-methylpiperazine 2,2,2-trifluoroacetate (46.9 mg, 0.126 mmol) in DCM (1.5 mL) and N,N-diisopropylethylamine (0.60 mL, 3.5 mmol). The resulting mixture was stirred at room temperature for 10 min before sodium triacetoxyborohydride (16 mg, 0.073 mmol) was added in one portion as a solid. The resulting mixture was stirred at room temperature for 58 h. The reaction mixture was concentrated in vacuo and the residue was dissolved and taken up in MeOH and subjected to preparative reverse-phase HPLC (Gemini™ Prep C18 10 μm column; Phenomenex, Torrance, Calif.; gradient elution of 20% to 90% MeCN in water, where both solvents contain 0.1% TFA, 15-min gradient in a 24 min method) to give, after lyophilization, (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-Chloro-7′-ethoxy-11′,12′-dimethyl-7′-(((3R)-3-methyl-4-(1-methylethyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (11.2 mg, 0.013 mmol, 70% yield) as a TFA salt as a white solid. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ 8.05 (br s, 1H), 7.71 (d, J=8.61 Hz, 1H), 7.17 (dd, J=2.25, 8.51 Hz, 1H), 7.08-7.13 (m, 2H), 6.90 (s, 2H), 5.94-6.08 (m, 1H), 5.55-5.64 (m, 1H), 4.20-4.29 (m, 1H), 4.08 (s, 2H), 3.85-3.92 (m, 2H), 3.70-3.83 (m, 2H), 3.62-3.68 (m, 1H), 3.46-3.58 (m, 3H), 3.33 (br d, J=4.50 Hz, 2H), 3.26 (d, J=14.28 Hz, 1H), 2.99 (br dd, J=10.07, 14.57 Hz, 2H), 2.73-2.87 (m, 3H), 2.57 (br dd, J=7.92, 14.18 Hz, 2H), 2.11-2.18 (m, 3H), 2.06 (br d, J=13.89 Hz, 2H), 1.86-1.98 (m, 4H), 1.79 (br d, J=8.02 Hz, 1H), 1.67 (br d, J=4.89 Hz, 2H), 1.37-1.45 (m, 13H), 1.24 (d, J=6.65 Hz, 3H), 1.01 (d, J=6.65 Hz, 3H). MS (ESI, +ve ion) m/z 781.2 (M+H)⁺.

Example 10 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-METHOXY-11′,12′-DIMETHYL-7′-((9AR)-OCTAHYDRO-2H-PYRIDO[1,2-A]PYRAZIN-2-YLMETHYL)-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO [14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE General Method 7 (Steps 1-2)

Step 1: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-7′-((9AR)-OCTAHYDRO-2H-PYRIDO[1,2-A]PYRAZIN-2-YLMETHYL)-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE

Preparation of amine free base: To a 150 mL round bottomed flask was added (R)-octahydro-1H-pyrido[1,2-a]pyrazine dihydrochloride (5.0 g, 23.5 mmol, WuXi) and methanol (30 mL). To the solution at room temperature was added sodium methoxide (25 wt % solution in methanol, 14.0 mL, 58.6 mmol) over 2 min. The solution was stirred at room temperature for 10 min and then concentrated. The material was treated with 2-methyltetrahydrofuran to form a suspension and then filtered. The filtrate was concentrated to form a viscous brown oil. The oil was treated with 2-methyltetrahydrofuran and heptane, filtered through a syringe filter and then concentrated to afford (R)-octahydro-1H-pyrido[1,2-a]pyrazine (3.4 g) as a brown semi-solid.

To a 250 mL 3-neck flask was added (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2′-oxiran]-15′-one 13′,13′-dioxide (4.75 g, 7.77 mmol), sodium tert-butoxide (1.49 g, 15.5 mmol), and 2-methyltetrahydrofuran (40 mL). To the solution was added (R)-octahydro-1H-pyrido[1,2-a]pyrazine (1.64 g, 11.7 mmol). The reaction mixture was then heated at 65° C. for 1 d. The solution was allowed to cool to room temperature and treated with pH 7 buffer (K₂HPO₄/KH₂PO₄ based). The solution was extracted with DCM (3×) and the combined extracts were washed with water and brine, dried over Na₂SO₄, and concentrated. The crude product, (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide, was carried on directly.

Step 2: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-METHOXY-11′,12′-DIMETHYL-7′-((9AR)-OCTAHYDRO-2H-PYRIDO[1,2-A]PYRAZIN-2-YLMETHYL)-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE

To a 250 mL flask containing (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-1′,12′-dimethyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo [14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (5.8 g, 7.7 mmol) was added 2-methyltetrahydrofuran (80 mL). The solution was cooled to 0° C. and potassium bis(trimethylsilyl)amide (1 M in THF, 19.3 mL, 19.3 mmol) was added over 5 min. After stirring for 10 min at 0° C., iodomethane (1.44 mL, 23.2 mmol) was added in one portion. The solution was stirred at 0° C. for 2 h and then additional potassium bis(trimethylsilyl)amide (4 mL) was added, stirred for 10 min and then additional iodomethane (0.48 mL) was added. The solution was stirred for 1 h at 0° C. and then aqueous pH 7 buffer (KH₂PO₄/K₂HPO₄ based) was added and the reaction mixture was allowed to warm to room temperature. The solution was extracted with DCM (3×) and the combined extracts were washed with brine, dried over Na₂SO₄, and concentrated onto silica. Purification by silica gel chromatography (10% to 60% EtOAc/heptane and then 5% to 10% MeOH/CH₂Cl₂) afforded (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide as an off-white solid (3.30 g, 4.31 mmol, 56% yield). ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 7.72 (d, J=8.6 Hz, 1H), 7.26 (d, J=1.4 Hz, 1H), 7.17 (dd, J=8.6, 2.2 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 6.92-6.99 (m, 1H), 6.89 (d, J=8.0 Hz, 1H), 5.64 (dt, J=15.7, 5.3 Hz, 1H), 5.42 (br d, J=16.4 Hz, 1H), 4.07 (s, 2H), 4.03 (br d, J=7.2 Hz, 1H), 3.98 (br d, J=14.9 Hz, 1H), 3.70 (br d, J=14.3 Hz, 1H), 3.34 (s, 3H), 3.23-3.30 (m, 1H), 3.06-3.22 (m, 2H), 2.90-3.01 (m, 1H), 2.74-2.81 (m, 2H), 2.65-2.73 (m, 2H), 2.52-2.62 (m, 4H), 2.28-2.35 (m, 1H), 2.16-2.26 (m, 2H), 2.03-2.15 (m, 3H), 1.81-1.99 (m, 6H), 1.71-1.79 (m, 2H), 1.57-1.71 (m, 4H), 1.47-1.56 (m, 2H), 1.34-1.44 (m, 5H), 1.02 (d, J=6.7 Hz, 3H). MS (ESI, +ve ion) m/z 765.3 (M+H)⁺.

Example 11 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide General Method 1 (Steps 3-7) and General Method 11 (Step 11)

Step 1: (3R,4S)-1-methoxy-N,N-bis(4-methoxybenzyl)-4-methylhept-6-ene-3-sulfonamide

A dry 2 L three neck flask with a thermo couple and magnetic stir bar under nitrogen was charged with (S)—N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-1-sulfonamide (54 g, 134 mmol) and 300 mL of dry toluene. Cooled solution to −76° C. internal temperature (acetone/dry ice bath). Added n-butyllithium solution (1.6 M in hexanes, 100 mL, 161 mmol) slowly via cannula under a positive pressure of nitrogen. The mixture was stirred at −78° C. for 1 hour. Then 2-bromoethyl methyl ether (18.88 mL, 201 mmol) was slowly via syringe. After the addition, the −78° C. bath was replaced with an ice water bath. After a total of 105 minutes reaction time, the reaction was quenched with saturated ammonium chloride at 0° C. The mixture was diluted with water and EtOAc and warmed to room temperature with stirring. The layers were separated and extracted with additional EtOAc. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude products were further separated to give 20.4 g of (3R,4S)-1-methoxy-N,N-bis(4-methoxybenzyl)-4-methylhept-6-ene-3-sulfonamide (44.2 mmol, 55% yield). MS (ESI, +ve ion) m/z 484.0 (M+Na)⁺.

Step 2: (3R,4S)-1-methoxy-4-methylhept-6-ene-3-sulfonamide

At 0° C., trifluoroacetic acid (164 mL, 2210 mmol) was added dropwise via addition funnel to a solution of (3R,4S)-1-methoxy-N,N-bis(4-methoxybenzyl)-4-methylhept-6-ene-3-sulfonamide (20.4 g, 44.2 mmol) and anisole (48.0 mL, 442 mmol) in DCM (221 mL). The solution was allowed to come to room temperature and stirred overnight. The reaction was concentrated in vacuo. The remaining material was partitioned between DCM and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. Purification by flash column chromatography on silica gel (eluted with 0% to 100% EtOAc in heptane) gave (3R,4S)-1-methoxy-4-methylhept-6-ene-3-sulfonamide (9.85 g, 44.5 mmol, 101% yield) as a light yellow oil. MS (ESI, +ve ion) m/z 243.9 (M+Na)⁺.

Step 3: (S)-5-(((1R,2R)-2-((S)-1-acetoxyallyl)cyclobutyl)methyl)-6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid

To a nitrogen inerted 3-neck 1 L flask equipped with a thermometer and a magnetic stir bar at room temperature was added 4-(dimethylamino) pyridine (0.821 g, 6.72 mmol), 2-methyltetrahydrofuran (80 mL), triethylamine (7.02 mL, 50.4 mmol), acetic anhydride (4.76 mL, 50.4 mmol), and a solution of (S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid (15.72 g, 33.6 mmol) in 2-methyltetrahydrofuran (80 mL) was added via cannula over 20 min (internal temperature increased from 20° C. to 25° C. during the addition). The reaction mixture was stirred at room temperature for 1.5 h. Water (40 mL) was added (internal temperature increased from 23° C. to 26° C.) followed by 1 M Na₂HPO₄ (60 mL). Sodium hydroxide (1 M, 20 mL, 220 mmol) was added until the pH reached 9. The mixture was stirred at room temperature for 19 h and the pH was adjusted to 3 with 2 M HCl (80 mL). The mixture was diluted with PhMe (150 mL) and transferred to a separatory funnel. The aqueous layer was discarded and the organic phase was washed with water (75 mL), 20% brine (75 mL), and concentrated under reduced pressure. The concentrate was diluted with PhMe (100 mL) and the PhMe was removed under reduced pressure. This was repeated three times to give (S)-5-(((1R,2R)-2-((S)-1-acetoxyallyl)cyclobutyl)methyl)-6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid as an orange oil that was used without further purification. MS (ESI, +ve ion) m/z 510.2 (M+H)⁺.

Step 4: (S)-1-((1R,2R)-2-(((S)-6′-chloro-7-((((3R,4S)-1-methoxy-4-methylhept-6-en-3-yl)sulfonyl)carbamoyl)-3′,4′-dihydro-2H,2′H-spiro [benzo[b][1,4]oxazepine-3,1′-naphthalen]-5(4H)-yl)methyl)cyclobutyl)allyl acetate

To a 1 L 3-neck flask was charged (S)-5-(((1R,2R)-2-((S)-1-acetoxyallyl)cyclobutyl)methyl)-6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid (28.73 g, 35.8 mmol) as a solution in toluene (228 mL). DMF (0.277 mL, 3.58 mmol) was added followed by slow addition of thionyl chloride (2.74 mL, 37.6 mmol) via syringe. The reaction was stirred at room temperature for 4 h and additional thionyl chloride (0.50 mL) was added and the reaction was stirred for 1 h. In a separate flask (3R,4S)-1-methoxy-4-methylhept-6-ene-3-sulfonamide (9.85 g, 42.5 mmol) and 4-(dimethylamino)pyridine (0.437 g, 3.58 mmol) were combined and azetroped by concentration in vacuo with PhMe (80 mL) and then taken up in 100 mL of PhMe. The resulting solution was added to the acid chloride solution described above via cannula. The solution was cooled in an ice bath for 10 min before triethylamine (17.41 mL, 125 mmol) was added dropwise via addition funnel. After the addition, the reaction was warmed to room temperature and stirred overnight. The reaction was quenched with saturated ammonium chloride. To the mixture was added 0.1 M aqueous HCl and then the mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrate in vacuo. Purification by flash column chromatography on silica gel (eluted with 0% to 100% EtOAc in heptane) gave (S)-1-((1R,2R)-2-(((S)-6′-chloro-7-((((3R,4S)-1-methoxy-4-methylhept-6-en-3-yl)sulfonyl)carbamoyl)-3′,4′-dihydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalen]-5(4H)-yl)methyl)cyclobutyl)allyl acetate (28.11 g, 39.4 mmol) as an orange foam that was used in the next step without further purification. MS (ESI, +ve ion) m/z 713.0 (M+H)⁺.

Step 5: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-12′-(2-methoxyethyl)-11′-methyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl acetate

To a 5 L reactor equipped with mechanical stirrer, thermo couple, nitrogen sparge tube, condenser, was charged 3.6 L of toluene. The PhMe was heated at 79° C. with sparging of nitrogen through the solution. In a separate flask, (S)-1-((1R,2R)-2-(((S)-6′-chloro-7-((((3R,4S)-1-methoxy-4-methylhept-6-en-3-yl)sulfonyl)carbamoyl)-3′,4′-dihydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalen]-5(4H)-yl)methyl)cyclobutyl)allyl acetate (25.14 g, 32.0 mmol) was azetroped with 300 mL of toluene and then dissolved in 1.2 L PhMe which was added via syringe pump over 2 h. Simultaneously, 4 charges of Umicore M73 SIMes (4×238 mg) (Umicore AG & Co. KG, Precious Metals Chemistry, Rodenbacher Chaussee 4, 63457 Hanau-Wolfgang, Germany) was added as a slurry in 5 mL PhMe. Each charge was added at intervals of 40 min. After 4 h, the reaction was cooled to 30° C. and di(ethylene glycol) vinyl ether (0.350 mL, 2.56 mmol) was added and the solution was stirred overnight with the sparge replaced with a nitrogen inlet. The reactor was drained and the volume of the reaction was reduced to 1 L. SilaMetS Thiol (70 g) (SiliCycle Inc. 2500, Parc-Technologique Blvd Quebec City, Quebec, Canada) was added and the mixture was stirred overnight. The mixture was filtered and the SilaMetS Thiol was washed with EtOAc and the filtrate was concentrated. Purification by flash column chromatography on silica gel (330 g Gold Rf, eluted with 0% to 100% EtOAc in heptane) gave (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-12′-(2-methoxyethyl)-11′-methyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl acetate (19.76 g, 28.8 mmol, 90% yield) as an orange oil. MS (ESI, +ve ion) m/z 685.0 (M+H)⁺.

Step 6: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Sodium methoxide (25% solution in methanol, 11.35 mL, 49.7 mmol) was added to a solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-12′-(2-methoxyethyl)-11′-methyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl acetate (19.76 g, 24.83 mmol) in toluene (100 mL) and methanol (20.00 mL) at room temperature. After 45 min, the reaction was quenched with citric acid (2 M aqueous solution, 37.2 mL, 74.5 mmol) and diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with 2× water, saturated aqueous sodium chloride, and dried over sodium sulfate. The mixture was filtered and concentrated in vacuo and dried overnight to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide as an orange oil. MS (ESI, +ve ion) m/z 643.0 (M+H)⁺.

Step 7: (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide

To a 1 L flask containing (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (19.1 g, 29.7 mmol), prepared in the previous step, was added DCM (300 mL). The solution was cooled in an ice bath for 20 min. Dess-Martin periodinane (15.11 g, 35.6 mmol) was added in one portion and the reaction was stirred while cooled in the ice bath for 40 min. The reaction was removed from the ice bath and stirred for 1.5 h at room temperature. Sodium thiosulfate was added followed by water and the mixture was stirred vigorously for 20 min. The reaction was diluted with saturated aqueous sodium bicarbonate and extracted with EtOAc (3×). The combined organic layers were washed with water and brine, dried with sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (eluted with 0% to 60% EtOAc in heptane) gave (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (14.29 g, 22.3 mmol, 75% yield) as a light yellow solid. MS (ESI, +ve ion) m/z 640.8 (M+H)⁺.

Step 8: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a 100 mL round-bottomed flask was added 1,3-dithiane (2.025 g, 16.84 mmol) in THF (42.1 mL). At −78° C., n-butyllithium (2.5 M solution in hexane, 5.90 mL, 14.7 mmol) was added to the solution. The solution was stirred for 15 min and then (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (2.70 g, 4.21 mmol) in 10 mL of THF was added slowly. The mixture was stirred for 1 h and 10 mL of saturated ammonium chloride was added to quench the reaction. The mixture was diluted with 1 N HCl (20 mL) and extracted with EtOAc (3×40 mL). The organic extracts were washed with saturated NaCl (40 mL) and dried over MgSO₄. The solution was filtered and concentrated in vacuo. The material was purified by chromatography through a Redi-Sep pre-packed silica gel column (80 g), eluting with a gradient of 0% to 60% EtOAc (with 0.1% HOAc) in heptane to give (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (1.6 g, 2.1 mmol, 50% yield). MS (ESI, +ve ion) m/z 761.1 (M+H)⁺.

Step 9: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-12′-(2-methoxy ethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a 100 mL round-bottomed flask was added (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (1.6 g, 2.1 mmol) and iodomethane (1.044 mL, 16.81 mmol) in THF (21 mL). At 0° C., sodium hydride (0.504 g, 21.0 mmol) was added portion wise. The reaction W was stirred at room temperature for 5 h. The reaction mixture was diluted with saturated NH₄Cl (20 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with saturated NaCl (15 mL) and dried over MgSO₄. The solution was filtered and concentrated in vacuo. Purification by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 60% EtOAc (with 0.1% HOAc) in heptane gave (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (0.93 g, 1.2 mmol, 57% yield) as an off-white solid. MS (ESI, +ve ion) m/z 775.1 (M+H)⁺.

Step 10: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide

To a resealable vial was added (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (0.93 g, 1.2 mmol), acetonitrile (9.6 mL) and water (2.4 mL). To the mixture was added calcium carbonate (0.600 g, 6.00 mmol) and iodomethane (0.745 mL, 12.0 mmol). The mixture was heated at 45° C. overnight. The solution was poured into saturated NH₄Cl and water and then extracted with EtOAc. The combined extracts were washed with brine and then dried over Na₂SO₄ and concentrated. Purification by silica gel chromatography (eluted with 0% to 60% EtOAc in heptane (with 0.1% AcOH) gave (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-1′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (0.70 g, 1.021 mmol, 85% yield) as a white solid. MS (ESI, +ve ion) m/z 685.1 (M+H)⁺.

Step 11: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a 100 mL round-bottomed flask was added (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (450 mg, 0.657 mmol), (S)-octahydropyrazino[2,1-c][1,4]oxazine HCl salt (1130 mg, 5.25 mmol) and N,N-diisopropylethylamine (2.341 mL, 13.13 mmol) in DCM (13.1 mL). Titanium(IV) isopropoxide (0.770 mL, 2.63 mmol) was added to the solution slowly. The reaction was stirred at room temperature overnight. Sodium triacetoxyborohydride (278 mg, 1.31 mmol) was added to the reaction portion wise and the mixture was stirred overnight. The reaction was diluted with saturated NaCl (20 mL). The white precipitate was removed by filtration through Celite. The filtrate was concentrated and diluted with 1 N HCl (20 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with saturated NaCl (50 mL) and dried over MgSO₄. The solution was filtered and concentrated in vacuo. The concentrate was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g, with a layer of sodium bicarbonate on top). Elution with a gradient of 0% to 10% methanol in DCM gave (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (420 mg, 0.518 mmol, 79% yield) as a white solid. MS (ESI, +ve ion) m/z 811.0 (M+H)⁺. 1H NMR (400 MHz, dichloromethane-d₂) δ ppm 0.91-1.10 (m, 3H), 1.33-1.72 (m, 10H, with water residue), 1.81-1.97 (m, 5H), 2.03-2.39 (m, 10H), 2.41-2.69 (m, 6H), 2.71-2.83 (m, 2H), 2.90-3.08 (m, 2H), 3.12-3.27 (m, 2H), 3.33 (s, 3H), 3.37 (s, 3H), 3.53-3.83 (m, 6H), 3.95-4.09 (m, 3H), 4.11-4.22 (m, 1H), 5.23-5.29 (m, 1H), 5.55-5.62 (m, 1H), 6.80-6.93 (m, 2H), 7.09 (s, 1H), 7.13-7.22 (m, 1H), 7.30 (s, 1H), 7.72 (d, J=8.41 Hz, 1H).

Example 12 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-7′-(((3R)-3-methyl-4-(1-methylethyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a 25 mL flask was added (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (80 mg, 0.117 mmol), (R)-1-isopropyl-2-methylpiperazine bis(2,2,2-trifluoroacetate) (330 mg, 0.891 mmol), N,N-diisopropylethylamine (366 μL, 2.10 mmol) and titanium(IV) isopropoxide (137 μL, 0.467 mmol) in DCM (2335 μL). The solution was stirred at room temperature overnight. To this solution was added sodium triacetoxyborohydride (99 mg, 0.47 mmol). The reaction was stirred for 24 h. The reaction mixture was diluted with 1 N HCl (10 mL) and extracted with DCM (2×20 mL). The organic solvent was concentrated. The residue was purified by prep-HPLC to give (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-7′-(((3R)-3-methyl-4-(1-methylethyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide as a TFA salt. MS (ESI, +ve ion) m/z 811.2 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ ppm 1.06 (d, J=6.06 Hz, 3H), 1.25-1.48 (m, 10H), 1.49-2.30 (m, 12H), 2.42-2.84 (m, 8H), 2.94-3.27 (m, 4H), 3.35 (s, 3H), 3.42 (s, 4H), 3.51-3.74 (m, 5H), 3.91-4.10 (m, 3H), 4.14-4.25 (m, 1H), 5.35 (d, J=16.04 Hz, 1H), 5.69-5.82 (m, 1H), 6.86-6.94 (m, 1H), 7.01 (dd, J=8.02, 1.76 Hz, 1H), 7.10 (d, J=1.96 Hz, 1H), 7.16 (dd, J=8.41, 2.15 Hz, 1H), 7.26 (d, J=1.37 Hz, 1H), 7.73 (d, J=8.61 Hz, 1H).

Example 13 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Step 1: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a 100 mL round-bottomed flask was added (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (0.62 g, 0.814 mmol) and iodoethane (0.655 mL, 8.14 mmol) in N, N-dimethylformamide (8.14 mL). At 0° C., potassium bis(trimethylsilyl)amide (1 M in THF, 8.14 mL, 8.14 mmol) was added slowly. The reaction was stirred overnight. The reaction mixture was diluted with 1 N HCl (15 mL) and extracted with EtOAc (3×15 mL). The organic extract was washed with saturated NaCl (15 mL) and dried over MgSO₄. The solution was filtered and concentrated in vacuo. The concentrate was absorbed onto a plug of silica gel and purified by chromatography through a 24 g ISCO gold column, eluted with a gradient of 0% to 40% EtOAc (with 0.1% of HOAc) in heptane, to provide (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (0.24 g, 0.304 mmol, 37% yield). MS (ESI, +ve ion) m/z 789.1 (M+H)⁺.

Step 2: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide

To a resealable vial was added (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (510 mg, 0.646 mmol), acetonitrile (5168 μL) and water (1292 μL). To the mixture was added calcium carbonate (323 mg, 3.23 mmol) and iodomethane (401 μL, 6.46 mmol). The mixture was heated at 45° C. overnight. The reaction was diluted with saturated NH₄Cl (10 mL) and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with saturated NaCl (20 mL) and dried over MgSO₄. The solution was filtered and concentrated in vacuo. The concentrate was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 60% EtOAc (with 0.1% of HOAc), to provide (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (230 mg, 0.329 mmol, 50.9% yield) as a white solid. MS (ESI, +ve ion) m/z 699.1 (M+H)⁺.

Step 3: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a 50-mL round-bottomed flask was added (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (150 mg, 0.215 mmol), (S)-octahydropyrazino[2,1-c][1,4]oxazine HCl salt (277 mg, 1.29 mmol) and N,N-diisopropylethylamine (574 μL, 3.22 mmol) in DCM (4290 μL). The reaction was stirred at room temperature overnight. Sodium triacetoxyborohydride (182 mg, 0.858 mmol) was added to the reaction mixture. The reaction was stirred for 8 h. The reaction mixture was diluted with 1 N HCl (20 mL) and extracted with DCM (2×20 mL). The organic layer was fully concentrated. The residue was further purified by prep-HPLC. The solution after pre-HPLC was washed with pH 7 solution and extracted with EtOAc (2×20 mL). The organic extract was washed with saturated NaCl (20 mL) and dried over MgSO₄. The solution was filtered and concentrated in vacuo to give (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide as a white solid. MS (ESI, +ve ion) m/z 825.2 (M+H)⁺. ¹H NMR (400 MHz, dichloromethane-d₂) δ ppm 1.01 (d, J=6.26 Hz, 3H), 1.35 (t, J=6.85 Hz, 3H), 1.44-1.74 (m, 7H), 1.77-2.01 (m, 5H), 2.04-2.38 (m, 9H), 2.41-2.65 (m, 5H), 2.70-2.83 (m, 2H), 2.86-3.08 (m, 2H), 3.27 (d, J=14.28 Hz, 1H), 3.35 (s, 3H), 3.40-3.49 (m, 1H), 3.52-3.83 (m, 7H), 3.99-4.10 (m, 3H), 4.12-4.28 (m, 1H), 5.35-5.42 (m, 1H), 5.57-5.76 (m, 1H), 6.85-6.92 (m, 2H), 7.09 (d, J=2.15 Hz, 1H), 7.13-7.20 (m, 1H), 7.24 (s, 1H), 7.72 (d, J=8.41 Hz, 1H).

Example 14 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide General Method 12

To a 25 mL flask was added (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (130 mg, 0.186 mmol) in DCM (3718 μL). To this solution was added 1-(oxetan-3-yl)piperazine (159 mg, 1.12 mmol) and a drop of acetic acid. The mixture was stirred for 8 h and sodium triacetoxyborohydride (158 mg, 0.744 mmol) was added. The reaction was stirred for 2 h and diluted with 1 N HCl (10 mL) and extracted with DCM (3×15 mL). The organic layer was concentrated. The concentrate was purified by prep-HPLC. The solution from prep-HPLC was washed with pH 7 buffer and extracted with EtOAc. The organic layer was concentrated to give (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide as a white solid. MS (ESI, +ve ion) m/z 825.2 (M+H)⁺. ¹H NMR (400 MHz, dichloromethane-d₂) δ ppm 0.98 (br s, 3H), 1.29-1.43 (m, 4H), 1.47-2.24 (m, 12H), 2.24-2.41 (m, 4H), 2.45-2.84 (m, 9H), 2.87-3.07 (m, 1H), 3.27 (br d, J=14.09 Hz, 1H), 3.34 (s, 3H), 3.39-3.52 (m, 2H), 3.57-3.76 (m, 4H), 3.95-4.20 (m, 4H), 4.45-4.55 (m, 2H), 4.57-4.65 (m, 2H), 5.38-5.51 (m, 1H), 5.59-5.74 (m, 1H), 6.89 (s, 2H), 7.09 (d, J=1.96 Hz, 1H), 7.13-7.19 (m, 1H), 7.21-7.28 (m, 1H), 7.72 (d, J=8.41 Hz, 1H).

Example 15 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a 25 mL flask was added (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (60 mg, 0.086 mmol) and (9ar)-octahydro-2h-pyrido[1,2-a]pyrazine (120 mg, 0.858 mmol) in DCM (1716 μL). A drop of acetic acid was added. The solution was stirred at room temperature overnight. To this solution was added sodium triacetoxyborohydride (73 mg, 0.34 mmol). The reaction was stirred for 8 h and diluted with 1 N HCl (10 mL) and extracted with DCM (2×10 mL). The solvent was removed under reduced pressure. The concentrate was purified by prep-HPLC to give (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide as a TFA salt. MS (ESI, +ve ion) m/z 823.2 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ ppm 1.05 (d, J=6.46 Hz, 3H), 1.37 (t, J=6.85 Hz, 3H), 1.41-2.02 (m, 14H), 2.04-2.26 (m, 5H), 2.30-2.51 (m, 2H), 2.51-2.87 (m, 6H), 2.92-3.08 (m, 3H), 3.11-3.26 (m, 2H), 3.35-3.54 (m, 7H), 3.60-3.78 (m, 4H), 3.94-4.11 (m, 3H), 4.18-4.29 (m, 1H), 5.43 (d, J=16.04 Hz, 1H), 5.67-5.89 (m, 1H), 6.87-6.94 (m, 1H), 6.95-7.03 (m, 1H), 7.10 (d, J=1.96 Hz, 1H), 7.14-7.19 (m, 1H), 7.24 (d, J=1.56 Hz, 1H), 7.73 (d, J=8.61 Hz, 1H).

Example 16 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-((4-(1-methylethyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a 10 mL flask was added 1-isopropylpiperazine (123 μL, 0.858 mmol) and (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (60 mg, 0.086 mmol) in DCM (1716 μL). A drop of acetic acid was added and the reaction was stirred overnight. Sodium triacetoxyborohydride (72.7 mg, 0.343 mmol) was added to the reaction mixture. The reaction was stirred at room temperature for 8 h. The reaction mixture was diluted with 1 N HCl (5 mL) and extracted with DCM (2×10 mL). The organic layer was concentrated. The concentrate was purified by prep-HPLC to give (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-((4-(1-methylethyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide as a TFA salt. MS (ESI, +ve ion) m/z 811.2 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ ppm 1.05 (d, J=6.46 Hz, 3H), 1.29-1.47 (m, 10H), 1.52-2.30 (m, 12H), 2.51-2.87 (m, 8H), 2.93-3.11 (m, 2H), 3.38 (s, 4H), 3.45-3.57 (m, 3H), 3.59-3.78 (m, 4H), 3.95-4.11 (m, 3H), 4.20-4.33 (m, 1H), 5.45 (d, J=15.85 Hz, 1H), 5.77-5.91 (m, 1H), 6.84-6.94 (m, 1H), 6.96-7.02 (m, 1H), 7.10 (d, J=1.96 Hz, 1H), 7.16 (br d, J=8.41 Hz, 1H), 7.23 (d, J=1.57 Hz, 1H), 7.73 (d, J=8.41 Hz, 1H).

Example 17 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-(((3R)-3-methyl-4-(1-methylethyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a 25 mL flask was added (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (80 mg, 0.11 mmol), (R)-1-isopropyl-2-methylpiperazine bis(2,2,2-trifluoroacetate) (254 mg, 0.686 mmol), N,N-diisopropylethylamine (408 μL, 2.29 mmol) and titanium(IV) isopropoxide (134 μL, 0.458 mmol) in DCM (2288 μL). The solution was stirred at room temperature for 8 h. To this solution was added sodium triacetoxyborohydride (97 mg, 0.46 mmol). The reaction was stirred overnight. The reaction mixture was diluted with 1 N HCl (10 mL) and extracted with DCM (2×10 mL). The solvent was concentrated. The residue was purified by prep-HPLC to give (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-(((3R)-3-methyl-4-(1-methylethyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide as a TFA salt. MS (ESI, +ve ion) m/z 825.4 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ ppm 1.05 (d, J=6.46 Hz, 3H), 1.21-1.49 (m, 13H), 1.51-2.28 (m, 12H), 2.37-2.87 (m, 8H), 2.92-3.20 (m, 3H), 3.36-3.57 (m, 7H), 3.60-3.79 (m, 4H), 3.97-4.07 (m, 3H) 4.20-4.31 (m, 1H), 5.43 (d, J=16.04 Hz, 1H), 5.75-5.90 (m, 1H), 6.87-6.94 (m, 1H), 6.98-7.01 (m, 1H), 7.10 (d, J=1.37 Hz, 1H), 7.14-7.19 (m, 1H), 7.24 (d, J=1.37 Hz, 1H), 7.73 (d, J=8.61 Hz, 1H).

Example 18 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide General Method 2 (Steps 10-12) and General Method 4 (Steps 13-14)

Step 1: (S,E)-(6-chloro-1-((hydroxyimino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl 4-bromobenzoate

To a stirred solution of (R)-(6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl 4-bromobenzoate (425 g, 1042 mmol) in DCM (5100 mL) and MeOH (5100 mL) under a nitrogen atmosphere was added pyridine (337 mL, 4170 mmol) followed by hydroxylamine hydrochloride (145 g, 2085 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was diluted with DCM (2.0 L) and the organic layer was washed with water (2.0 L). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield (S,E)-(6-chloro-1-((hydroxyimino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl 4-bromobenzoate as yellow liquid. The material was used in the next step without further purification. ¹H NMR (400 MHz, Chloroform-d) δ 7.85-7.80 (dd, J=8.7, 2.1 Hz, 2H), 7.58-7.55 (m, 2H), 7.51 (s, 1H), 7.23-7.26 (m, 1H), 7.14-7.16 (m, 2H), 4.66-4.64 (d, J=11.3 Hz, 1H), 4.56-4.53 (d, J=11.2 Hz, 1H), 2.84-2.81 (t, J=6.3 Hz, 2H), 2.14-2.02 (dddd, J=14.8, 13.2, 7.1, 3.8 Hz, 2H), 1.96-1.83 (dddt, J=13.9, 11.8, 5.9, 3.7 Hz, 2H).

Step 2: (S)-(1-(aminomethyl)-6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methanol hydrochloride

(S,E)-(6-Chloro-1-((hydroxyimino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl 4-bromobenzoate (425 g, 1005 mmol), prepared in the previous step, was dissolved in THF (5160 mL) under a nitrogen atmosphere. The reaction mixture was cooled to 0° C. and lithium aluminum hydride (1.0 M in THF, 3519 mL, 3519 mmol) was added drop-wise. The ice-bath was removed and the reaction mixture was stirred at room temperature for 3 h. The reaction was cooled to 0° C. and water (160 mL) was added slowly, followed by 15% aqueous NaOH solution (160 mL) and water (500 mL). The mixture was allowed to stir for 10 min at room temperature and the reaction was filtered. The residual solids were washed with hot ethyl acetate (3×4.0 L). The combined filtrate was concentrated under reduced pressure to yield a yellow oil. The residue was dissolved in DCM (5160 mL) and the solution was cooled to 0° C. A solution of HCl (4.0 M in dioxane, 65 mL) was added drop-wise and mixture was allowed to stir for 15 min at room temperature. The precipitate was collected by filtration. The solid was washed with ice-cold DCM (100 mL) and dried to afford (S)-(1-(aminomethyl)-6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methanol hydrochloride (192 g, 72.8% yield). ¹H NMR (400 MHz, Methanol-d₄) δ 7.38-7.36 (d, J=8.2 Hz, 1H), 7.23-7.20 (m, 2H), 3.81-3.78 (m, 1H), 3.69-3.68 (dd, J=10.9, 1.3 Hz, 1H), 3.48-3.45 (d, J=13.1 Hz, 1H), 3.23-3.20 (d, J=13.2 Hz, 1H), 2.83-2.81 (d, J=6.3 Hz, 2H), 2.17-2.11 (m, 1H), 1.91-1.85 (m, 2H), 1.83-1.74 (m, 1H); exchangeable protons not observed.

Step 3: (S)-methyl 5-((1-(aminomethyl)-6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-6-bromopicolinate

To a stirred solution of (S)-(1-(aminomethyl)-6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methanol hydrochloride (150 g, 572 mmol) was dissolved in dry DMSO (2250 mL) under a nitrogen atmosphere at room temperature. The solution was treated with 6-bromo-5-fluoropicolinic acid (151 g, 687 mmol) and the resulting solution was treated with potassium 2-methylpropan-2-olate (218 g, 1945 mmol) at room temperature. The reaction mixture was stirred for 2 h at room temperature and quenched by addition of acetic acid (˜170 mL) at room temperature, followed by water (1.5 L) which resulted in precipitation of a solid. The solid was collected by filtration, washed with water (1.0 L), and dried. The solid was added to a pre-mixed solution of MeOH/H₂SO₄ (10:1, v/v, 5400 mL) and stirred at 80° C. for 3 h. The mixture was cooled to room temperature and solid K₂CO₃ (600 g) was slowly added to quench the sulfuric acid. The mixture was suspended in water (2 L) and ethyl acetate (2 L). The layers were separated. The aqueous layer was extracted with ethyl acetate (2×2.5 L). The combined organic extracts were washed with brine (2.0 L), dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. Purification by column chromatography on silica gel (60-120 mesh, eluted with 0% to 5% MeOH in DCM) gave (S)-methyl 5-((1-(aminomethyl)-6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-6-bromopicolinate (170 g, 67.6% yield) as off-white solid. MS (ESI, +ve ion) m/z 439.0 (M+1). ¹H NMR (400 MHz, Chloroform-d) δ 8.06-8.04 (dd, J=8.4, 1.0 Hz, 1H), 7.51-7.49 (d, J=8.4 Hz, 1H), 7.18-7.14 (m, 3H), 4.18-4.11 (m, 2H), 3.93 (s, 3H), 3.25-3.17 (m, 2H), 2.80-2.76 (m, 2H), 2.06-1.97 (m, 2H), 1.94-1.85 (tdd, J=9.5, 6.7, 4.2 Hz, 2H); exchangeable protons not observed.

Step 4: methyl 5-(((S)-1-(((((1R,2R)-2-(acetoxymethyl)cyclobutyl)methyl)amino)methyl)-6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-6-bromopicolinate

To a stirred solution of (S)-methyl 5-((1-(aminomethyl)-6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-6-bromopicolinate (170 g, 387 mmol) in dry DCM (1.7 L) and acetic acid (1105 mL) under a nitrogen atmosphere was added ((1R,2S)-2-((S)-(1H-benzo[d][1,2,3]triazol-1-yl)(hydroxy)methyl)cyclobutyl)methyl acetate (128 g, 464 mmol) followed by sodium cyanoborohydride (31.6 g, 503 mmol) at 0° C. The reaction was maintained at 0° C. for 2 h. The reaction was poured slowly into cold 10% sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (2×2.0 L). The combined organic layer was washed with brine (1.0 L) and dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography on silica gel (60-120 mesh, eluted with 2% to 5% MeOH in DCM) gave methyl 5-(((S)-1-(((((1R,2R)-2-(acetoxymethyl)cyclobutyl)methyl)amino)methyl)-6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-6-bromopicolinate (149 g, 66.5% yield) as yellow liquid. MS (ESI, +ve ion) m/z 579.1 (M+1). ¹H NMR (400 MHz, Chloroform-d) δ 8.08-8.06 (dt, J=8.4, 1.3 Hz, 1H), 7.55-7.53 (dd, J=8.3, 1.6 Hz, 1H), 7.19-7.13 (m, 3H), 4.13 (s, 2H), 4.10-4.00 (t, J=2.3 Hz, 2H), 3.98 (d, J=1.4 Hz, 3H), 3.05-2.98 (m, 2H), 2.79-2.78 (m, 2H), 2.69-2.58 (m, 2H), 2.18-2.11 (dd, J=8.9, 4.9 Hz, 2H), 2.09-2.06 (dq, J=9.7, 4.8, 3.1 Hz, 1H), 2.00 (t, J=1.3 Hz, 3H), 1.97-1.82 (m, 6H), 1.65-1.61 (d, J=9.2 Hz, 1H), 1.59-1.51 (q, J=8.9 Hz, 1H).

Step 5: (S)-methyl 5′-(((1R,2R)-2-(acetoxymethyl)cyclobutyl)methyl)-6-chloro-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate

A solution of methyl 5-(((S)-1-(((((1R,2R)-2-(acetoxymethyl)cyclobutyl)methyl)amino)methyl)-6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-6-bromopicolinate (36 g, 62.1 mmol) and N-ethyl-N-isopropylpropan-2-amine (161 mL, 933 mmol) in N-methyl-2-pyrrolidinone (360 mL) was stirred at 130° C. under a nitrogen atmosphere for 16 h. The reaction was cooled to room temperature and diluted with ethyl acetate (1.0 L). The mixture was washed with water (5×400 mL). The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography on silica gel (60-120 mesh, 0% to 10% EtOAc in hexane) gave (S)-methyl 5′-(((1R,2R)-2-(acetoxymethyl)cyclobutyl)methyl)-6-chloro-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate (16 g, 51.7% yield) as yellow liquid. MS (ESI, +ve ion) m/z 499.1 (M+1). ¹H NMR (400 MHz, Chloroform-d) δ 7.72-7.70 (d, J=8.5 Hz, 1H), 7.46-7.44 (dd, J=7.9, 1.1 Hz, 1H), 7.21-7.20 (dd, J=8.5, 2.2 Hz, 1H), 7.18-7.11 (m, 2H), 4.18-4.15 (d, J=12.2 Hz, 1H), 4.05-3.98 (m, 3H), 3.95-3.93 (d, J=4.5 Hz, 1H), 3.91-3.89 (d, J=1.0 Hz, 3H), 3.74-3.70 (d, J=14.5 Hz, 1H), 3.42-3.32 (m, 2H), 2.79-2.76 (dt, J=9.0, 5.1 Hz, 2H), 2.55-2.49 (dt, J=15.5, 7.4 Hz, 2H), 1.98-1.85 (m, 8H), 1.76-1.74 (t, J=9.4 Hz, 1H), 1.62-1.61 (d, J=1.1 Hz, 1H), 1.50-1.49 (d, J=1.1 Hz, 1H).

Step 6: (S)-methyl 6-chloro-5′-(((1R,2R)-2-(hydroxymethyl)cyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate

To a stirred solution of (S)-methyl 5′-(((1R,2R)-2-(acetoxymethyl)cyclobutyl)methyl)-6-chloro-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate (68 g, 136 mmol) in THF (680 mL) and water (680 mL) was added lithium hydroxide monohydrate (22.87 g, 545 mmol) at room temperature. The reaction was allowed to stir at room temperature for 12 h. The reaction was concentrated under reduced pressure and the residue was taken up in MTBE (1.0 L), 10% citric acid monohydrate solution (500 mL) was added and the solution was stirred for 10 min. The layers were separated and the organic layer was washed with brine (500 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was dissolved in dry methanol (600 mL) and cooled to 0° C. Thionyl chloride (14.92 mL, 204 mmol) was added and the reaction was heated at 60° C. for 12 h. The reaction was cooled to 0° C. and quenched by slow addition of 10% sodium bicarbonate solution (500 mL) and extracted with ethyl acetate (2×500 mL). The combined organic layer was washed with brine (300 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was suspended in acetonitrile (140 mL) and water (140 mL) was added. The mixture was stirred for 10 min. The solid was collected by filtration and dried to give (S)-methyl 6-chloro-5′-(((1R,2R)-2-(hydroxymethyl)cyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate (58 g, 93% yield). MS (ESI, +ve ion) m/z 457.1 (M+1). ¹H NMR (400 MHz, Chloroform-d) δ 7.73-7.72 (d, J=8.5 Hz, 1H), 7.47-7.45 (d, J=7.9 Hz, 1H), 7.21-7.19 (dd, J=8.5, 2.3 Hz, 1H), 7.14-7.11 (m, 2H), 4.44-4.40 (m, 1H), 4.16-4.13 (d, J=12.1 Hz, 1H), 4.06-4.03 (d, J=12.1 Hz, 1H), 3.95 (s, 3H), 3.84-3.80 (d, J=14.4 Hz, 1H), 3.75-3.68 (m, 1H), 3.57-3.56 (ddt, J=14.1, 9.3, 4.2 Hz, 2H), 3.37-3.36 (d, J=14.5 Hz, 1H), 2.96-2.90 (dd, J=14.0, 9.1 Hz, 1H), 2.82-2.76 (m, 2H), 2.58-2.54 (m, 1H), 2.32 (td, J=12.2, 10.4, 6.3 Hz, 1H), 2.02-1.95 (m, 3H), 1.88-1.83 (m, 2H), 1.67-1.55 (m, 2H), 1.49-1.43 (m, 1H).

Step 7: (S)-methyl 6-chloro-5′-(((1R,2R)-2-formylcyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate

A 1 L 3-neck flask equipped with a mechanical stir bar and a temperature probe was charged with DCM (220 mL, 5V) followed by oxalyl chloride (10.16 mL, 116 mmol). The solution was cooled to −73° C. in a dry-ice acetone bath. DMSO (17.15 mL, 242 mmol) was added via syringe over 7 min (internal temperature increased from −74° C. to −60° C. during the addition). The mixture was held for 14 min and a solution of (S)-methyl 6-chloro-5′-(((1R,2R)-2-(hydroxymethyl)cyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro [naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate (44.2 g, 97 mmol) in DCM (220 mL, 5V) cooled in a dry-ice acetone bath was added via cannula over 12 min (internal temperature increased from −75° C. to −72° C. during the addition). The solution was stirred for 17 min and triethylamine (67.4 mL, 484 mmol) was added over 7 min (internal temperature increased from −76° C. to −65° C. during the addition). After the addition of the Et₃N, the reaction was held in the dry ice acetone bath for 5 min then warmed to 7° C. over 4 h and quenched with water (220 mL, 5V) (internal temperature increased from 7° C. to 15° C. during the quench). The mixture was transferred to a separatory funnel and the aqueous layer was discarded. The bottom layer was washed with saturated NH₄Cl (220 mL, 5V), 1:1 water:saturated NaHCO₃ (220 mL, 5V), and 1:1 water:brine (220 mL, 5V). The bottom organic layer was dried over MgSO₄, filtered through a fine frit, and concentrated under reduced pressure to give an off white foam. The foam was dissolved in 1:1 EtOAc/DCM (100 mL) and filtered through a 2 cm pad of silica (eluted with 400 mL of 1:1 EtOAc/DCM). The solution was concentrated under reduced pressure, diluted with PhMe (100 mL) and concentrated. This was repeated twice more and the product (S)-methyl 6-chloro-5′-(((1R,2R)-2-formylcyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate was used without further purification. MS (ESI, +ve ion) m/z 454.9 (M+H)⁺.

Step 8: (1S)-methyl 6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate

To a 2 L jacketed reactor was charged (−)-cinchonidine (5.69 g, 19.34 mmol) followed by PhMe (220 mL, 5V) and THF (220 mL, 5V). The solution was cooled to −23° C. (internal temperature) and zinc chloride (1.9 M in 2-methyltetrahydrofuran, 81 mL, 155 mmol) was added over 3 min (internal temperature increased from −23° C. to −19° C. during the addition). The solution was stirred for 5 min and vinylmagnesium chloride (1.6 M solution in THF, 206 mL, 329 mmol) was added via an addition funnel over 24 min (internal temperature increased from −21° C. to −13° C. during the addition). The solution was stirred for 20 min (internal temperature decreased to −22° C.) and a solution of (S)-methyl 6-chloro-5′-(((1R,2R)-2-formylcyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate, prepared in the previous step, in PhMe (220 mL, 5V) cooled in an ice-water bath was added via cannula over 8 min (internal temperature increased from −22° C. to −16° C. during the addition). The reaction was stirred at −20° C. for 1 h and warmed to 0° C. After 45 min, the reaction was cooled to −8° C. and quenched with saturated NH₄Cl (350 mL, 8V). Water (88 mL, 2V) was added. Ammonium hydroxide (20 mL, 0.45V) was added and the solids dissolved. The aqueous phase was discarded. The organic phase was washed with saturated NH₄Cl (220 mL, 5 V), 1 M citric acid (4×88 mL, 2V), 1:1 water:brine (440 mL, 10V), dried over MgSO₄, filtered, and concentrated to give a yellow oil. MeOH (200 mL) was added and removed under reduced pressure. This was repeated a second time and the product (1S)-methyl 6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate was used without further purification as a mixture of diastereomers. MS (ESI, +ve ion) m/z 483.0 (M+H)⁺.

Step 9: (1S)-6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylic acid

To a 2 L jacketed reactor was charged a solution of (1S)-methyl 6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylate, prepared in the previous step, in MeOH (234 mL, 5V) and THF (234 mL, 5V). Lithium hydroxide monohydrate (16.23 g, 387 mmol) was added and the reaction was stirred at room temperature for 17 h. Citric acid (1 M in water, 180 mL) was added followed by water (187 mL, 4V) and EtOAc (234 mL, 5V). All the solids dissolved. The mixture was drained from the reactor into a 3 L flask and the mixture was concentrated to half the original volume. EtOAc (234 mL, 5V) was added and the mixture was transferred to a separatory funnel. The pH of the aqueous layer was 5. The aqueous layer was discarded. The organic layer was washed with 1:1 water:brine (235 mL, 5V), dried over MgSO₄, filtered, and concentrated to give 47.0 g of a yellow solid that was 79 wt % (1S)-6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylic acid (37.1 g, 79 mmol, 82% yield) and a mixture of diastereomers. MS (ESI, +ve ion) m/z 469.0 (M+H)⁺.

Step 10: (1S)-6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-N-(((2R,3 S)-3-methylhex-5-en-2-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide

To a mixture of (1S)-6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylic acid (34.7 g, 58.5 mmol), 4-(dimethylamino)pyridine (21.42 g, 175 mmol), and (2R,3S)-3-methylhex-5-ene-2-sulfonamide (21.41 g, 117 mmol) in a 500 mL 1-neck flask was added PhMe (100 mL). The PhMe was removed under reduced pressure and the concentrate was diluted with DCM (347 mL, 10V) and transferred to a 3-neck 1 L flask equipped with a temperature probe and a magnetic stirrer. Triethylamine (24.44 mL, 175 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (22.41 g, 117 mmol) were added and the reaction was stirred at room temperature. After 43 h, the reaction was diluted with water (240 mL, 7V) and transferred to a separatory funnel. The pH of the aqueous phase was adjusted to 4 with 1 M citric acid (240 mL, 7V) and the aqueous phase was discarded. The organic phase was washed with 1:1 brine:water (240 mL, 7V), dried over MgSO₄, filtered, and concentrated. Purification by flash column chromatography on silica gel (330 g silica, eluted with 50% to 100% DCM in heptane) gave (1S)-6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-N-(((2R,3 S)-3-methylhex-5-en-2-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide (24.7 g, 39.3 mmol, 67% yield) as a pale yellow foam and a mixture of diastereomers. MS (ESI, +ve ion) m/z 628.0 (M+H)⁺.

Step 11: (S)-5′-(((1R,2R)-2-acryloylcyclobutyl)methyl)-6-chloro-N-(((2R,3S)-3-methylhex-5-en-2-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide

A solution of (1S)-6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-N-(((2R,3 S)-3-methylhex-5-en-2-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide (2.82 g, 4.49 mmol) in DCM (28 mL, 10V) in a 100 mL 1-neck flask equipped with a temperature probe and magnetic stir bar was cooled to 2° C. in an ice-water bath and Dess-Martin periodinane (2.094 g, 4.94 mmol) was added in one portion. The reaction was warmed to room temperature over 20 min and stirred at room temperature for 30 min. The solution was cooled to 2° C. in a water-ice bath and quenched with a solution of sodium thiosulfate (2.4 g) in water (8.4 mL, 3V) followed by saturated NaHCO₃ (20 mL, 7V). The internal temperature increased from 2° C. to 7° C. during the quench. The reaction was removed from the water-ice bath, warmed to room temperature, and stirred for 30 min. The mixture was transferred to a separatory funnel. The pH was adjusted to 7 with 1 M citric acid. The aqueous layer was discarded. The organic phase was washed with 1:1 water:brine (28 mL, 10V), dried over MgSO₄, filtered, and concentrated to give a yellow foam. The concentrate was dissolved in 10% EtOAc in DCM (˜50 mL) and filtered through a 1 cm pad of silica gel (eluted with ˜100 mL of 10% EtOAc in DCM). The filtrate was concentrated to give (S)-5′-(((1R,2R)-2-acryloylcyclobutyl)methyl)-6-chloro-N-(((2R,3 S)-3-methylhex-5-en-2-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide as a pale yellow foam that was used without further purification. MS (ESI, +ve ion) m/z 625.8 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.14 (d, J=6.85 Hz, 3H), 1.45 (d, J=7.04 Hz, 3H), 1.48-1.56 (m, 1H), 1.81-2.05 (m, 6H), 2.10-2.19 (m, 2H), 2.27 (q, J=8.80 Hz, 1H), 2.62 (qd, J=7.14, 2.45 Hz, 1H), 2.73-2.87 (m, 2H), 3.04-3.17 (m, 1H), 3.30 (q, J=8.80 Hz, 1H), 3.36-3.43 (m, 1H), 3.43-3.47 (m, 1H), 3.78 (d, J=14.48 Hz, 1H), 3.89-4.07 (m, 3H), 4.20 (d, J=12.32 Hz, 1H), 5.07-5.15 (m, 2H), 5.74-5.87 (m, 2H), 6.15-6.32 (m, 2H), 7.12 (d, J=2.15 Hz, 1H), 7.18-7.22 (m, 2H), 7.58 (d, J=7.83 Hz, 1H), 7.69 (d, J=8.41 Hz, 1H), 9.90 (s, 1H).

Step 12: (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraene]-7′,15′-dione 13′,13′-dioxide

To a 4-neck flask equipped with a magnetic stir bar, a temperature probe, and an air cooled condenser was charged PhMe (1.8 L, 250V). The solvent was heated to 80° C. and a gas dispersion tube was immersed into the solvent. Nitrogen gas was bubbled through the solvent via the gas dispersion tube. A solution of (S)-5′-(((1R,2R)-2-acryloylcyclobutyl)methyl)-6-chloro-N-(((2R,3S)-3-methylhex-5-en-2-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide (8.93 g, 80 wt %, 11.41 mmol) in PhMe (65 mL) was added via an addition funnel over 2 h. During the addition of the diene, Umicore M73 SIMes (Umicore AG & Co. KG, Precious Metals Chemistry, Rodenbacher Chaussee 4, 63457 Hanau-Wolfgang, Germany) was added in four equal portions (total amount of catalyst was 0.346 g, 0.456 mmol) as a suspension in PhMe (4 mL) via syringe at: t=0 min, t=30 min, t=60 min, and t=90 min. After the addition of the diene was complete, the reaction was stirred for an additional 1 h at 80° C. The reaction was cooled to room temperature and 2-(2-(vinyloxy)ethoxy)ethanol (0.125 mL, 0.913 mmol) and SilaMetS Thiol (SiliCycle Inc. 2500, Parc-Technologique Blvd Quebec City, Quebec, Canada) (7.71 g) were added. The mixture was stirred at room temperature for 18 h and the SilaMetS Thiol was removed by filtration and washed with EtOAc and concentrated to give a tan color solid. MeOH (˜50 mL) was added and removed under reduced pressure. MeOH (107 mL, 15V) was added and the slurry was stirred at room temperature for 3 d and collected by filtration. The solid was washed with MeOH (1×40 mL) and dried on a frit under a vacuum with a positive flow of nitrogen to give 6.39 g of an off white solid that was 66 wt % (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (4.22 g, 7.0 mmol, 62% yield). MS (ESI, +ve ion) m/z 598.1 (M+H)⁺.

Step 13: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide

To a 3-neck flask equipped with temperature probe, septum, and nitrogen inlet was charged (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (6.33 g, 66 wt %, 6.98 mmol) and trimethylsulfonium iodide (2.138 g, 10.48 mmol). DMSO (35 mL) and THF (8.75 mL) were added and the mixture was stirred at room temperature for 20 min until the solids dissolved. The solution was cooled in an ice-water bath. When the internal temperature reached 6.5° C., potassium tert-butoxide (1.0 M solution in THF, 17.46 mL, 17.46 mmol) was added slowly via syringe. After 40 min, a small amount of trimethylsulfonium iodide was added followed by potassium tert-butoxide (1 M solution in THF, 1.2 mL, 1.2 mmol). After 15 minutes, zinc(II) trifluoromethanesulfonate (0.5 M in MeOH, 84 mL, 41.9 mmol) was added over 5 min. After addition, the reaction was warmed to room temperature, stirred for 2 h and quenched with saturated ammonium chloride (˜150 mL). Water and EtOAc were added. The aqueous phase was extracted with EtOAc (3×). The combined organic extracts were concentrated. The concentrate was dissolved in EtOAc, washed with water (2×), brine (1×), dried over Na₂SO₄, filtered, and concentrated. The material was absorbed onto silica gel. Purification by flash column chromatography (330 g silica, eluted with 10% to 80% EtOAc (2% AcOH) in heptane) gave 5.17 g of a light yellow solid that was 57 wt % (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide (2.93 g, 4.55 mmol, 65% yield). MS (ESI, +ve ion) m/z 644.0 (M+H)⁺.

Step 14: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide

To a solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide (79 wt %, 7.4 g, 9.07 mmol) in DCM (60 mL) and DMSO (30 mL) was added N,N-diisopropylethylamine (7.92 mL, 45.4 mmol). The solution was cooled in an ice water bath and pyridine-sulfur trioxide complex (3.61 g, 22.69 mmol) was added. After 40 min, the reaction was quench with saturated ammonium chloride and diluted water and EtOAc. The organic phase was washed with water. The combined aqueous phase was extracted with EtOAc (2×). The combined organic phase was washed with 50% saturated ammonium chloride (2×), brine, dried over Na₂SO₄, filtered, and concentrated to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide which was used without further purification. MS (ESI, +ve ion) m/z 641.9 (M+H)⁺.

Step 15: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide

To a solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-5′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (5.28 g, 8.22 mmol) and (S)-octahydropyrazino[2,1-c][1,4]oxazine (3.51 g, 24.67 mmol) in DCM (82 mL) at room temperature was added acetic acid (0.475 mL, 8.22 mmol). The mixture was stirred at room temperature for 1 h and sodium triacetoxyborohydride (2.091 g, 9.87 mmol) was added slowly over 1 min. After 1 h, additional sodium triacetoxyborohydride (300 mg) was added. The reaction was stirred for 30 min and quenched with saturated NH₄Cl. The aqueous phase was extracted with DCM (3×). The combined organic extracts were washed with saturated NH₄Cl (1×), brine (1×), dried over Na₂SO₄, filtered, and concentrated. Purification by flash column chromatography (330 g silica, eluted with 0% to 10% MeOH in DCM) gave (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide (6.02 g, 7.83 mmol, 95% yield) as off-white solid. MS (ESI, +ve ion) m/z 768.2 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.17 (d, J=6.85 Hz, 3H), 1.46 (d, J=7.04 Hz, 3H), 1.48-1.63 (m, 4H), 1.68-2.09 (m, 8H), 2.19 (br d, J=17.22 Hz, 1H), 2.49 (br s, 3H), 2.33 (br s, 3H), 2.42 (br s, 1H), 2.55-2.70 (m, 2H), 2.77-3.04 (m, 6H), 3.08 (s, 3H), 3.15 (br s, 1H), 3.54 (br s, 1H), 3.66 (br s, 1H), 3.74-3.96 (m, 2H), 3.95-3.95 (m, 1H), 4.02 (d, J=12.32 Hz, 1H), 4.09-4.21 (m, 2H), 5.51 (br d, J=17.02 Hz, 1H), 5.64 (br d, J=16.82 Hz, 1H), 7.11-7.17 (m, 2H), 7.21 (dd, J=8.51, 2.25 Hz, 1H), 7.38 (d, J=7.82 Hz, 1H), 7.67 (d, J=8.61 Hz, 1H), 9.12 (br s, 1H).

Example 19 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide General Method 13

To a solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (12 mg, 0.019 mmol) and 1-(oxetan-3-yl)piperazine (26.6 mg, 0.187 mmol) in DCM (374 μL) at room temperature was added a few drop of titanium (IV) isopropoxide. The mixture was stirred at room temperature for 8 h and sodium triacetoxyborohydride (15.84 mg, 0.075 mmol) was added slowly over 1 min. The reaction was stirred for overnight and quenched with 5 mL of 1 N HCl solution. The aqueous phase was extracted with DCM (3×). The combined organic extracts were concentrated. The residue was purified by prep-HPLC to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide as a TFA salt. MS (ESI, +ve ion) m/z 768.2 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ ppm 1.11 (d, J=6.65 Hz, 3H), 1.39 (d, J=7.24 Hz, 3H), 1.44-1.58 (m, 1H,) 1.64-2.01 (m, 6H), 2.03-2.27 (m, 2H), 2.29-2.43 (m, 2H,) 2.45-2.56 (m, 1H), 2.32-3.04 (m, 7H), 3.35-3.67 (m, 6H), 3.35-3.65 (m, 6H), 3.72-3.93 (m, 4H), 4.03-4.10 (m, 1H), 4.12-4.28 (m, 2H), 4.61 (t, J=6.16 Hz, 2H), 4.69-4.77 (m, 2H), 5.78-5.90 (m, 2H), 7.12 (d, J=1.96 Hz, 1H), 7.15-7.20 (m, 1H), 7.21-7.26 (m, 2H), 7.70 (d, J=8.41 Hz, 1H).

Example 20 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide

Step 1: (1S)-6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-N-(((3R,4S)-1-methoxy-4-methylhept-6-en-3-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide

To a solution of (3R,4S)-1-methoxy-4-methylhept-6-ene-3-sulfonamide (4.94 g, 22.34 mmol) in DCM (80 mL) was added (1S)-6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxylic acid (6.8 g, 11.5 mmol), 4-(dimethylamino) pyridine (4.20 g, 34.4 mmol), triethylamine (3.2 mL, 23.0 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (6.6 g, 34.4 mmol). The resulting mixture was stirred at room temperature under nitrogen for 20 h. The reaction was quenched with 2 N HCl (5 mL) and diluted with water (30 mL). The aqueous layer was extracted with DCM (2×40 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated. The crude product was purified by column chromatography (330 g of silica, 0% to 40% acetone in heptane) to obtain (1S)-6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-N-(((3R,4S)-1-methoxy-4-methylhept-6-en-3-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide as light brown solid (6.1 g). ¹H NMR (DICHLOROMETHANE-d₂) δ 10.43 (br. S., 1H), 7.70 (d, J=8.4 Hz, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.19 (d, J=7.8 Hz, 2H), 7.10 (s, 1H), 5.67-5.87 (m, 2H), 5.19 (d, J=17.2 Hz, 1H), 5.01-5.12 (m, 3H), 4.60 (d, J=13.7 Hz, 1H), 4.10-4.20 (m, 1H), 3.96-4.07 (m, 3H), 3.89 (d, J=14.7 Hz, 1H), 3.53 (t, J=6.4 Hz, 1H), 3.43-3.50 (m, 1H), 3.34-3.42 (m, 1H), 3.19-3.25 (m, 2H), 3.13 (s, 1H), 2.82-2.92 (m, 1H), 2.73-2.82 (m, 2H), 2.55-2.69 (m, 1H), 2.37-2.48 (m, 1H), 2.33 (br. S., 1H), 2.04-2.22 (m, 3H), 1.91-2.01 (m, 4H), 1.76-1.91 (m, 2H), 1.62-1.74 (m, 1H), 1.54-1.61 (m, 1H), 1.41 (t, J=12.8 Hz, 1H), 1.07 (dd, J=11.2, 7.0 Hz, 3H). MS (ESI, +ve ion) m/z 672.4 (M+H)⁺.

Step 2: (S)-5′-(((1R,2R)-2-acryloylcyclobutyl)methyl)-6-chloro-N-(((3R,4S)-1-methoxy-4-methylhept-6-en-3-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide

To a solution of (1S)-6-chloro-5′-(((1R,2R)-2-(1-hydroxyallyl)cyclobutyl)methyl)-N-(((3R,4S)-1-methoxy-4-methylhept-6-en-3-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide (6.1 g, 9.07 mmol) in DCM (70 mL) at 0° C. was added Dess-Martin periodinane (4.5 g, 10.61 mmol). After the addition, the ice bath was removed and the resulting mixture was warmed up to room temperature and stirred for 20 h. The reaction was quenched with 10% sodium thiosulfate (5 mL) and stirred for 30 min. The resulting mixture was washed with saturated NaHCO₃ (30 mL). The aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated. The crude product was purified by column chromatography (330 g of silica, 0% to 40% acetone in heptane) to obtain (S)-5′-(((1R,2R)-2-acryloylcyclobutyl)methyl)-6-chloro-N-(((3R,4S)-1-methoxy-4-methylhept-6-en-3-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide as light brown foam. ¹H NMR (DICHLOROMETHANE-d₂) δ 9.25-9.54 (m, 1H), 7.70-7.76 (m, 1H), 7.44-7.51 (m, 1H), 7.14-7.21 (m, 1H), 7.03-7.13 (m, 2H), 5.85-6.03 (m, 2H), 4.13-4.22 (m, 1H), 4.01-4.12 (m, 2H), 3.85-3.99 (m, 1H), 3.72-3.81 (m, 1H), 3.58-3.70 (m, 2H), 3.29-3.33 (m, 7H), 3.17-3.27 (m, 6H), 2.94-3.04 (m, 3H), 2.83-2.93 (m, 4H), 2.73-2.80 (m, 2H), 2.51-2.64 (m, 1H), 2.32-2.41 (m, 1H), 2.23-2.31 (m, 1H), 2.05-2.12 (m, 2H), 1.97-2.05 (m, 1H), 1.87-1.96 (m, 2H), 1.76-1.87 (m, 2H), 1.61-1.70 (m, 2H), 1.51-1.59 (m, 5H), 1.40-1.51 (m, 2H), 1.04-1.11 (m, 5H), 0.96-1.02 (m, 3H). MS (ESI, +ve ion) m/z 670.2 (M+H)⁺.

Step 3: (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraene]-7′,15′-dione 13′,13′-dioxide

To a solution of (S)-5′-(((1R,2R)-2-acryloylcyclobutyl)methyl)-6-chloro-N-(((3R,4S)-1-methoxy-4-methylhept-6-en-3-yl)sulfonyl)-3,4,4′,5′-tetrahydro-2H,2′H-spiro[naphthalene-1,3′-pyrido[3,2-b][1,4]oxazepine]-7′-carboxamide (2.2 g, 3.28 mmol) in 1,2-dichloroethane (1200 mL) under nitrogen was added Hoveyda-Grubbs catalyst 2^(nd) generation (0.206 g, 0.328 mmol). The resulting mixture was heated at 55° C. for 20 h. The reaction was cooled to room temperature and concentrated. The crude product was purified by column chromatography (220 g of silica, 0% to 30% acetone in heptane) to obtain (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraene]-7′,15′-dione 13′,13′-dioxide as pale yellow solid (1.5 g). ¹H NMR (DICHLOROMETHANE-d₂) δ 8.69 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.08-7.18 (m, 3H), 6.71-6.82 (m, 1H), 5.86-5.96 (m, 1H), 4.44 (dd, J=14.1, 8.4 Hz, 1H), 4.14 (d, J=12.1 Hz, 1H), 3.99 (d, J=12.1 Hz, 1H), 3.92 (d, J=15.3 Hz, 1H), 3.85-3.89 (m, 1H), 3.73-3.82 (m, 1H), 3.70 (dd, J=8.0, 5.1 Hz, 1H), 3.59-3.66 (m, 1H), 3.42 (s, 3H), 3.39 (d, J=14.7 Hz, 1H), 2.94 (dd, J=14.0, 3.8 Hz, 1H), 2.82-2.90 (m, 1H), 2.72-2.82 (m, 2H), 2.35-2.45 (m, 1H), 2.26-2.34 (m, 1H), 2.09-2.19 (m, 3H), 1.97-2.06 (m, 2H), 1.75-1.94 (m, 5H), 1.37-1.48 (m, 1H), 1.18 (d, J=6.8 Hz, 3H). MS (ESI, +ve ion) m/z 642.2 (M+H)⁺.

Step 4: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide

An oven dry 50 mL 3-neck flask, which was equipped with stir bar and temperature probe, was added 1,3-dithiane (0.890 g, 7.40 mmol) and THF (15 mL). The resulting mixture was cooled between −20 to −30° C. and n-butyllithium solution (2.5 M in hexanes, 2.7 mL, 6.75 mmol) was added dropwise via syringe. The resulting mixture was stirred at −20° C. for 30 min, cooled below −70° C. and stirred for 20 min. To this reaction was added lanthanum(III) chloride lithium chloride complex (0.6 M in THF, 5.6 mL, 3.36 mmol, Strem Chemical, Newbury Port, Mass.) dropwise via syringe (internal temperature was kept below −70° C.). After 10 min, (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (0.430 g, 0.670 mmol) in THF (5 mL) was added dropwise via syringe (internal temperature was kept below −70° C.). The reaction was stirred at −70° C. for 15 min after the addition. The reaction was quenched with saturated NH₄Cl (3 mL), warmed to room temperature and partitioned between EtOAc (60 mL) and water (30 mL). The organic layer was dried over MgSO₄, filtered, and concentrated. Purification by column chromatography (80 g of silica, 0% to 30% acetone in heptane) gave (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide as white solid (0.350 g). ¹H NMR (DICHLOROMETHANE-d₂) δ 9.24 (br. S., 1H), 7.65-7.73 (m, 1H), 7.35-7.41 (m, 1H), 7.19 (d, J=7.8 Hz, 2H), 7.11 (s, 1H), 5.76-5.87 (m, 1H), 5.60-5.71 (m, 1H), 4.61 (dd, J=13.5, 4.9 Hz, 1H), 4.12-4.22 (m, 2H), 3.94-4.03 (m, 2H), 3.89 (d, J=14.5 Hz, 1H), 3.53-3.63 (m, 2H), 3.44 (d, J=14.5 Hz, 1H), 3.32 (s, 3H), 2.94-3.04 (m, 2H), 2.85-2.93 (m, 4H), 2.73-2.84 (m, 3H), 2.54-2.70 (m, 2H), 2.17-2.33 (m, 2H), 2.04-2.13 (m, 4H), 1.87-2.00 (m, 3H), 1.71-1.83 (m, 3H), 1.64 (dt, J=18.6, 9.5 Hz, 1H), 1.47 (d, J=14.9 Hz, 1H), 1.15 (d, J=6.8 Hz, 3H). MS (ESI, +ve ion) m/z 762.2 (M+H)⁺.

Step 5: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-12′-(2-methoxy ethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide

To a 15 mL flask was added (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide (0.350 g, 0.459 mmol) and THF (15.0 mL). The mixture was cooled to 0° C. and sodium hydride (60 weight percent in oil, 0.165 g, 4.13 mmol) was added. The ice bath was removed after the addition and the mixture was stirred at room temperature for 20 min then iodomethane (0.520 mL, 8.37 mmol) was added. The mixture was stirred at room temperature for 2 h then quenched with water (5 mL). The resulting mixture was partitioned between EtOAc (50 mL) and water (20 ml). The organic layers was dried over MgSO₄, filtered, and concentrated. Purification by column chromatography (40 g of silica, 0% to 30% acetone in heptane) gave (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide as white solid. ¹H NMR (DICHLOROMETHANE-d₂) δ 9.20 (br. S., 1H), 7.69 (d, J=8.4 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.16-7.22 (m, 2H), 7.11 (s, 1H), 5.73-5.86 (m, 1H), 5.49-5.60 (m, 1H), 4.82 (dd, J=14.0, 5.0 Hz, 1H), 4.37 (s, 1H), 4.09-4.20 (m, 2H), 3.99 (d, J=12.3 Hz, 1H), 3.91 (d, J=14.5 Hz, 1H), 3.56-3.71 (m, 2H), 3.40-3.50 (m, 1H), 3.33 (s, 3H), 3.22 (s, 3H), 3.09 (br. S., 1H), 2.92-3.00 (m, 1H), 2.83-2.91 (m, 4H), 2.75-2.83 (m, 2H), 2.66-2.74 (m, 1H), 2.63 (br. S., 1H), 2.17-2.33 (m, 2H), 2.04-2.14 (m, 3H), 1.91 (td, J=11.7, 3.6 Hz, 4H), 1.71-1.80 (m, 1H), 1.62-1.70 (m, 2H), 1.54-1.62 (m, 1H), 1.39-1.49 (m, 1H), 1.15 (d, J=6.8 Hz, 3H). MS (ESI, +ve ion) m/z 776.2 (M+H)⁺.

Step 6: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide

To a solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo [14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (0.250 g, 0.322 mmol) in acetonitrile (12.0 mL) was added calcium carbonate (0.161 g, 1.610 mmol), water (3.00 mL), and iodomethane (0.250 mL, 4.02 mmol). The resulting mixture was heated at 40° C. for 20 h. The reaction was partitioned between water (20 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (30 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated. The purification by column chromatography (24 g of silica, 0% to 30% acetone in heptane) gave (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide as white solid (0.130 g). ¹H NMR (DICHLOROMETHANE-d₂) δ 9.74 (s, 1H), 9.50 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.21 (d, J=8.0 Hz, 2H), 7.12 (d, J=2.2 Hz, 1H), 5.69 (d, J=16.2 Hz, 1H), 5.38-5.47 (m, 1H), 4.42 (dd, J=14.0, 8.5 Hz, 1H), 4.19 (d, J=12.3 Hz, 1H), 4.04 (d, J=12.1 Hz, 1H), 3.87 (d, J=14.7 Hz, 1H), 3.60 (td, J=8.7, 4.9 Hz, 1H), 3.46-3.54 (m, 2H), 3.38-3.45 (m, 1H), 3.31 (s, 3H), 3.06 (s, 3H), 2.96 (dd, J=14.1, 5.9 Hz, 1H), 2.74-2.90 (m, 4H), 2.46 (ddd, J=11.2, 7.1, 3.7 Hz, 1H), 2.21-2.28 (m, 1H), 2.11-2.20 (m, 1H), 1.97-2.08 (m, 2H), 1.81-1.96 (m, 5H), 1.67-1.79 (m, 1H), 1.55-1.66 (m, 1H), 1.40-1.50 (m, 1H), 1.14 (d, J=6.8 Hz, 3H). MS (ESI, +ve ion) m/z 686.2 (M+H)⁺.

Step 7: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide

To a solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (0.080 g, 0.117 mmol) in DCM (4.0 mL) was added (S)-octahydropyrazino[2,1-c][1,4]oxazine (0.093 g, 0.653 mmol) in DCM (4.0 mL) and acetic acid (1 drop). The mixture was stirred at room temperature under nitrogen for 1 h. Sodium triacetoxyborohydride (0.100 g, 0.472 mmol) was added and the mixture was stirred at room temperature for 1 h. The reaction was partitioned between water (10 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (20 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated. Purification by column chromatography (24 g of silica, 0% to 10% MeOH in DCM) gave (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-12′-(2-methoxy ethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide as white solid (0.066 g). ¹H NMR (DICHLOROMETHANE-d₂) δ 7.70 (d, J=8.4 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.08-7.16 (m, 2H), 5.53-5.66 (m, 2H), 4.13-4.19 (m, 1H), 4.02-4.12 (m, 2H), 3.74-3.83 (m, 2H), 3.65-3.73 (m, 1H), 3.53-3.63 (m, 3H), 3.46 (d, J=14.7 Hz, 1H), 3.32 (s, 4H), 2.98-3.10 (m, 7H), 2.74-2.85 (m, 2H), 2.72 (d, J=6.1 Hz, 1H), 2.52-2.64 (m, 3H), 2.46 (d, J=16.8 Hz, 3H), 2.23-2.37 (m, 2H), 2.06-2.15 (m, 1H), 1.96-2.03 (m, 2H), 1.85-1.94 (m, 4H), 1.72-1.81 (m, 2H), 1.45-1.63 (m, 6H), 1.08 (d, J=6.8 Hz, 3H). One exchangeable proton was not observed. MS (ESI, +ve ion) m/z 812.4 (M+H)⁺.

Example 21 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide

To a solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (0.140 g, 0.204 mmol) in DCM (5.0 mL) was added (R)-octahydro-1H-pyrido[1,2-a]pyrazine (0.160 g, 1.141 mmol) in DCM (1 mL) and AcOH (2 drops). The mixture was stirred at room temperature under nitrogen for 1 h then treated with sodium triacetoxyborohydride (0.173 g, 0.816 mmol). The resulting mixture was stirred for 1 h then partitioned between water (10 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (20 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated. Purification by column chromatography (24 g of silica, 0% to 10% MeOH in DCM) gave (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-12′-(2-methoxyethyl)-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14,25]triazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide as white solid (0.120 g). ¹H NMR (DICHLOROMETHANE-d₂) δ 7.69-7.76 (m, 1H), 7.42-7.50 (m, 1H), 7.18 (dd, J=8.5, 2.1 Hz, 1H), 7.04-7.14 (m, 2H), 5.77 (br. S., 2H), 4.17 (d, J=12.9 Hz, 1H), 4.00-4.13 (m, 2H), 3.77 (d, J=14.5 Hz, 1H), 3.64-3.73 (m, 1H), 3.57 (d, J=9.2 Hz, 2H), 3.35-3.47 (m, 1H), 3.21-3.34 (m, 5H), 3.09 (br. S., 3H), 2.99 (br. S., 1H), 2.83-2.95 (m, 2H), 2.65-2.82 (m, 5H), 2.55 (br. S., 2H), 2.25-2.44 (m, 3H), 2.09-2.21 (m, 1H), 1.97-2.08 (m, 3H), 1.89 (d, J=19.2 Hz, 4H), 1.61-1.73 (m, 4H), 1.38-1.51 (m, 4H), 1.29-1.35 (m, 1H), 1.17 (br. S., 2H), 1.02 (d, J=6.8 Hz, 4H). One exchangeable proton was not observed. MS (ESI, +ve ion) m/z 810.4 (M+H)⁺.

Example 33 (1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′-ethyl-7′-methoxy-14′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Step 1: (1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′-ethyl-7′-methoxy-14′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide

A 2-dram vial was charged with (1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-12′-ethyl-7′-methoxy-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (27 mg, 0.037 mmol; Accessed via General Methods 1 (R¹=H, using (S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid and (R)-hept-6-ene-3-sulfonamide) and General Methods 5 (using MeI)), a magnetic stir bar, acetonitrile (820 μL) and water (205 μL). To the resulting suspension was added calcium carbonate (18.5 mg, 0.185 mmol) and iodomethane (23 μL, 0.37 mmol). The vial was sealed and the mixture stirred at 45° C. Additional iodomethane (10 equiv) was added after 2.5 h, 19 h, 23 h, and 27 h. After a 51 h reaction time, the reaction was quenched by adding saturated aqueous ammonium chloride (1 mL) and water (1 mL). The mixture was extracted with EtOAc (3×2 mL) and the combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford a mixture of (1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′-ethyl-7′-methoxy-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide and (1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′-ethyl-7′-methoxy-14′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide in a 3:1 ratio that was carried forward in the next step without purification.

Step 2: (1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′-ethyl-7′-methoxy-14′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

A 1 mL vial was charged with a 3:1 mixture of (1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′-ethyl-7′-methoxy-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide and (1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′-ethyl-7′-methoxy-14′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (0.022 g, 0.034 mmol), (R)-octahydro-1H-pyrido[1,2-a]pyrazine (26.5 mg, 0.189 mmol; Aurum Pharmatech, Franklin Park, N.J.), a magnetic stir bar, and 1,2-dichloroethane (343 μL). The resulting mixture was stirred for 1 h before the addition of sodium triacetoxyborohydride (3.6 mg, 0.017 mmol). After 45 min, a second portion of sodium triacetoxyborohydride (3.6 mg, 0.017 mmol) was added and the reaction was continued for an additional 2 h before a third portion of sodium triacetoxyborohydride (3.6 mg, 0.017 mmol) was added. After an additional 3 h, the reaction was quenched by adding methanol. (1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′-ethyl-7′-methoxy-14′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide was isolated as the corresponding TFA salt after purification via RP-HPLC (Column: Phenomenex Luna, C18, 150×21 mm; Solvent: A=water (0.1% TFA), B=(R) (0.1% TFA), 30 mL/min, 30% B to 100% B over 18 min then 2 min at 100% B): 5.2 mg (0.006 mmol, 17% yield); MS (ESI, +ve ion) m/z 779.3 (M+H)⁺.

Example 34 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(((2-(4-morpholinyl)ethyl)amino)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide General Method 13

A solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-15′-oxo-7′-methoxy-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (52 mg, 0.081 mmol) and 2-morpholinoethanamine (106 μL, 0.811 mmol) in THF (810 μL) was stirred at ambient temperature for 90 min. Sodium cyanotrihydroborate (25.5 mg, 0.405 mmol) and acetic acid (93 μL, 1.6 mmol) were added and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with EtOAc (2 mL) and washed with saturated aqueous sodium bicarbonate (5 mL); the layers were partitioned and the aqueous layer was washed with EtOAc (2×5 mL). The organic extracts were combined, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo to afford an off-white solid. (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(((2-(4-morpholinyl)ethyl)amino)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide was isolated as the corresponding TFA salt after purification via RP-HPLC (Column: Phenomenex Luna, C18, 150×21 mm; Solvent: A=water (0.1% TFA), B=(R) (0.1% TFA), 30 mL/min, 30% B to 100% B over 18 min then 2 min at 100% B): 41.8 mg (0.048 mmol, 59% yield); MS (ESI, +ve ion) m/z 755.2 (M+H)⁺.

Example 99 (1S,3′R,6′R,7′S,8′E,9a″S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one 13′,13′-dioxide

Step 1: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a room temperature mixture of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (0.050 g, 0.080 mmol) and (R)-morpholin-3-ylmethanol hydrochloride (0.124 g, 0.807 mmol; J&W Pharmlab, Levittown, Pa.) was added N,N-diisopropylethylamine (0.230 mL, 1.32 mmol) via syringe. After 30 min, 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.400 mL, 0.400 mmol) and acetic acid (0.100 mL, 1.73 mmol) were added and the reaction was allowed to stir at room temperature overnight. The reaction mixture was quenched with satd NH₄Cl and the aqueous layer was extracted with DCM (3×). The combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco, (4 gram HP)) eluting with 0% to 100% 2 M NH₃ in MeOH in DCM to give 70 mg of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide as a white crystalline solid. (ESI, +ve ion) m/z 728.3 (M+1)+.

Step 2: (1S,3′R,6′R,7′S,8′E,9a″S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one 13′,13′-dioxide

To a room temperature solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide in tetrahydrofuran (0.3 mL) was added 60% sodium hydride in mineral oil (0.011 g, 0.275 mmol) as a solid. After 30 min the mixture was cooled (0° C.) and treated with 1-(p-toluenesulfonyl)imidazole (0.064 g, 0.288 mmol) and the reaction was allowed to warm to room temperature overnight. The reaction mixture was quenched with saturated NH₄Cl and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco, (4 gram HP)) eluting with 2 M NH₃ in MeOH:CH₂C12 (0:1-1:9) to afford (1S,3′R,6′R,7′S,8′E,9a″S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one 13′,13′-dioxide (2.1 mg, 9%) as a tan crystalline solid. MS (ESI, +ve ion) m/z 710.3 (M+1)⁺.

Example 100 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3S)-3-(1H-imidazol-1-ylmethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Step 1: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3S)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a room temperature mixture of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (0.052 g, 0.083 mmol) and 3(S)-hydroxymethylmorpholine (0.099 g, 0.845 mmol; J&W Pharmlab, Levittown, Pa.) in tetrahydrofuran (2 mL) was added N,N-diisopropylethylamine (0.250 mL, 1.437 mmol). After 1 h, 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.450 mL, 0.450 mmol) and acetic acid (0.100 mL, 1.73 mmol) were added and the reaction was stirred overnight. The reaction mixture was quenched with pH 7 buffer and the aqueous layer was extracted with DCM (3×). The combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco (4 g)) eluting with 25% EtOH/EtOAc:heptane (0:1-1:1) to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3S)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (46 mg, 76%) as a white crystalline solid. (ESI, +ve ion) m/z 728.2 (M+1)⁺.

Step 2: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3S)-3-(1H-imidazol-1-ylmethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a room temperature solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3S)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide in tetrahydrofuran (1 mL) was added sodium hydride (0.020 g, 0.51 mmol) as a solid. After 30 min the reaction was cooled (0° C.) and treated with 1-(p-toluenesulfonyl)imidazole (0.112 g, 0.505 mmol). After stirring overnight the reaction mixture was quenched with pH 7 buffer and the aqueous layer was extracted with DCM (3×). The combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco (4 g)) eluting with 25% EtOH/EtOAc:heptane (0:1-1:0) to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3S)-3-(1H-imidazol-1-ylmethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (27 mg, 55%) as a white crystalline solid. (ESI, +ve ion) m/z 778.3 (M+1)⁺.

Example 105 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

A mixture of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (0.010 g, 0.013 mmol) and palladium, 10 wt. % (dry basis) on activated carbon, wet, degussa type (0.005 g, 2.3 μmol) in EtOAc (1 mL) was stirred at room temperature under hydrogen (18 psig) overnight. The reaction was filtered through a pad of Celite and the pad was washed with EtOAc. The filtrate was concentrated under reduced pressure, diluted with MeOH and purified by reverse-phase HPLC (Gilson; Gemini-NX C18 AXIA, 100×50 mm column) eluting with 0.1% TFA-H₂O:0.1% TFA CH₃CN (9:1-1:9). The fractions containing the desired product were combined and partitioned between pH 7 buffer (1 M K₂HPO₄/KH₂PO₄)/EtOAc. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were washed with brine, dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (6.5 mg, 68%) as a white crystalline solid. (ESI, +ve ion) m/z: 747.3 (M+1)⁺.

Example 124 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-4″,11′,12′-trimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one 13′,13′-dioxide

Step 1: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide and (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide

Calcium carbonate (2.60 g, 18.5 mmol) and iodomethane (1 M in TBME; 18.5 mL, 37.1 mmol) were sequentially added to a solution of (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide and (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (2.66 g, 3.71 mmol) in acetonitrile (44 mL)/water (6.5 mL) at 50° C.; the reaction mixture was stirred at 50° C. for 16 h. The slurry was filtered to remove any excess calcium carbonate, and the filtrate was concentrated. The solid was diluted with EtOAc (150 mL); the milky mixture was poured off; the remaining solid was diluted with DCM/IPA (3:2, 200 mL), and the combined organics were partitioned with sat. aq. NH₄Cl (100 mL). The organic layer was separated, solubilized with MeOH, dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude product was adsorbed onto silica gel and was purified via automated flash chromatography (silica gel, 0% to 50% EtOAc/heptane w/0.3% AcOH) to give (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-1′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (396 mg, 0.631 mmol, 17% yield) and (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (0.810, 1.29 mmol, 35% yield), both as white solids. MS (ESI, +ve) m/z 627.2 (M+1)⁺ for both.

Step 2: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((methylamino)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

A mixture of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (48 mg, 0.077 mmol), methanamine hydrochloride (91 mg, 1.3 mmol), and DIPEA (227 μL, 1.30 mmol) in DCM (383 μL)/MeOH (580 μL) was stirred at room temperature for 15 min; sodium cyanotrihydroborate (14 mg, 0.23 mmol) was then added. The slurry was stirred at room temperature for 30 min. The reaction mixture was diluted with DCM (50 mL), added to a separatory funnel, and washed with water (50 mL); the organic layer was separated, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The crude product was adsorbed onto silica gel and was purified via automated flash chromatography (silica gel, 0% to 20% MeOH/DCM) to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((methylamino)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (14 mg, 0.022 mmol, 29% yield) as a white film. MS (ESI, +ve) m/z 642.2 (M+1)⁺.

Step 3: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-4″,11′,12′-trimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one 13′,13′-dioxide

Cesium carbonate (85 mg, 0.26 mmol) was added to a solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((methylamino)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (14 mg, 0.022 mmol) and 1,2-dibromoethane (8 μL, 0.09 mmol) in DMF (0.22 mL) at ambient temperature. The reaction mixture was stirred at 70° C. for 16 h. 1-Tosyl-1H-imidazole (4.8 mg, 0.022 mmol) and sodium hydride (60% in mineral oil; 0.5 mg, 0.02 mmol) were added to the reaction mixture which was then stirred at ambient temperature for 20 min. The reaction mixture was diluted with EtOAc (50 mL), added to a separatory funnel, and washed with saturated, aqueous sodium bicarbonate (2×50 mL); the organic layer was separated, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The crude product was adsorbed onto silica gel and was purified via automated flash chromatography (silica gel, 0% to 10% MeOH/DCM) to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-4″,11′,12′-trimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one 13′,13′-dioxide (2 mg, 3 μmol, 14% yield) as a light yellow oil. MS (ESI, +ve) m/z 668.3 (M+1)⁺.

Example 125 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-((tert-butylamino)methyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

A solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (99 mg, 0.16 mmol) and 2-methylpropan-2-amine (115 mg, 1.58 mmol) in THF (1.6 mL) was stirred at ambient temperature for 1.5 h; sodium cyanotrihydroborate (50 mg, 0.79 mmol) and acetic acid (181 μL, 3.16 mmol) were added, and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with EtOAc (75 mL), added to a separatory funnel, and washed with saturated, aqueous sodium bicarbonate (100 mL); the organic layer was separated, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The crude product was adsorbed onto silica gel and was purified via automated flash chromatography (silica gel, 0% to 10% MeOH/DCM) to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-((tert-butylamino)methyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (53 mg, 0.077 mmol, 49% yield) as a white solid. MS (ESI, +ve) m/z 684.3 (M+1)⁺.

Example 126 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((2-hydroxyethyl)(1-methylethyl)amino)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

A solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (68 mg, 0.11 mmol) and 2-(isopropylamino)ethanol (Enamine, Monmouth Jct, N.J.; 112 mg, 1.08 mmol) in THF (1.1 mL) was stirred at ambient temperature for 2.5 h; sodium cyanotrihydroborate (34 mg, 0.54 mmol) and acetic acid (0.1 mL, 2.2 mmol) were added, and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with EtOAc (75 mL), added to a separatory funnel, and washed with saturated, aqueous sodium bicarbonate (100 mL); the organic layer was separated, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The crude product was adsorbed onto silica gel and was purified via automated flash chromatography (silica gel, 0% to 8% MeOH/DCM) to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((2-hydroxyethyl)(1-methylethyl)amino)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (20 mg, 0.028 mmol, 26% yield) as a white solid. MS (ESI, +ve) m/z 714.2 (M+1)⁺.

Example 127 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-4″-(1-methylethyl)-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one 13′,13′-dioxide

Sodium hydride (60% in mineral oil; 3 mg, 0.07 mmol) was added to a solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((2-hydroxyethyl)(1-methylethyl)amino)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (17 mg, 0.024 mmol) and 1-tosyl-1H-imidazole (6.9 mg, 0.031 mmol) in THF (0.24 mL) at 0° C.; the reaction mixture was stirred at 0° C. for 15 min. The reaction mixture was diluted with EtOAc (75 mL), added to a separatory funnel, and washed with saturated, aqueous ammonium chloride (100 mL); the organic layer was separated, dried over anhydrous Na₂SO₄, and concentrated in vacuo. A solution of the crude product in DCM was loaded onto the column and was purified via automated flash chromatography (silica gel, 0% to 6% MeOH/DCM) to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-4″-(1-methylethyl)-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one 13′,13′-dioxide (6 mg, 9 μmol, 36% yield) as a white solid. MS (ESI, +ve) m/z: 696.3 (M+1)⁺.

Example 128 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,2″H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,5″-[1,3]oxazolidine]-2″,15′-dione 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,2″H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,5″-[1,3]oxazolidine]-2″,15′-dione 13′,13′-dioxide

Step 1: methyl ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate and methyl ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate

A solution of methyl acetate (0.172 mL, 2.17 mmol) in THF (1 mL) was added dropwise to a stirred solution of lithium diisopropylamide (1.0 M solution in hexanes/tetrahydrofuran, 2.17 mL, 2.17 mmol) in THF (1 mL) at −78° C. The mixture was stirred at −78° C. for 0.5 h before a solution of (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (216 mg, 0.362 mmol) in THF (2 mL) was added slowly via syringe. The reaction mixture was stirred at −78° C. for 1.5 h before being allowed to warm to room temperature and quenched with water (15 mL). The mixture was extracted with EtOAc (25 mL). The organic layer was separated, washed with 1 M aqueous HCl (15 mL), washed with brine (15 mL), dried over MgSO₄, filtered, and concentrated in vacuo to give a crude mixture of methyl ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate and methyl ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate (246 mg, 0.366 mmol, 101% yield) as a yellow solid that was used directly in the next step. MS (ESI, +ve ion) m/z 671.3 (M+H)⁺.

Step 2: ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetic acid and ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetic acid

Lithium hydroxide (2.0 M aqueous, 0.453 mL, 0.905 mmol) was added to a stirred solution of methyl ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate and methyl ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate (243 mg, 0.362 mmol) in tetrahydrofuran (7 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous NH₄Cl (30 mL) and extracted three times with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO₄, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc with 0.3% AcOH as a modifier in heptane) gave the desired product contaminated with AcOH. The isolated product was azeotroped with toluene to give a mixture of ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetic acid and ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetic acid (66 mg, 0.100 mmol, 27.7% yield) as a white solid. MS (ESI, +ve ion) m/z 657.2 (M+H)⁺.

Step 3: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,2″H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,5″-[1,3]oxazolidine]-2″,15′-dione 13′,13′-dioxide or (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,2″H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,5″-[1,3]oxazolidine]-2″,15′-dione 13′,13′-dioxide

A mixture of ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetic acid and ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetic acid (66 mg, 0.100 mmol), triethylamine (0.031 mL, 0.221 mmol), and diphenylphosphoryl azide (0.024 mL, 0.110 mmol) in tert-butanol (2 mL) was refluxed for 2.5 h. The reaction mixture was concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc with 0.3% AcOH as a modifier in heptane) provided (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,2″H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,5″-[1,3]oxazolidine]-2″,15′-dione 13′,13′-dioxide or (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,2″H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,5″-[1,3]oxazolidine]-2″,15′-dione 13′,13′-dioxide (30 mg, 0.046 mmol, 45.7% yield) as a white solid. MS (ESI, +ve ion) m/z 654.2 (M+H)⁺.

Example 138 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-4″-benzyl-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one 13′,13′-dioxide

Step 1: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((2-hydroxyethyl)amino)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

A mixture of (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-5′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (199 mg, 0.317 mmol) and 2-aminoethanol (322 mg, 5.27 mmol) was stirred in dichloromethane (6 mL) for 20 min before acetic acid (0.366 mL, 6.35 mmol) and sodium cyanoborohydride (59.8 mg, 0.952 mmol) were added. The reaction mixture was stirred at room temperature for 17 h. The reaction mixture was quenched with saturated aqueous NH₄Cl (40 mL) and extracted with EtOAc (50 mL). The organic layer was separated, washed with brine (30 mL), dried over MgSO₄, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 10% 2 M ammonia in MeOH in DCM) provided (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((2-hydroxyethyl)amino)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (115 mg, 0.171 mmol, 53.9% yield) as a white solid. MS (ESI, +ve ion) m/z 672.2 (M+H)⁺.

Step 2: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one 13′,13′-dioxide

Sodium hydride (60% dispersion in mineral oil, 20.5 mg, 0.513 mmol) was added to a stirred suspension of (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((2-hydroxyethyl)amino)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (115 mg, 0.171 mmol) in tetrahydrofuran (5 mL) at room temperature. The mixture was stirred for 20 min before being cooled to 0° C., followed by addition of 1-(p-toluenesulfonyl)imidazole (38.0 mg, 0.171 mmol). The reaction mixture was stirred at 0° C. for 5 h. The reaction mixture was quenched with saturated aqueous NH₄Cl (20 mL) and extracted with EtOAc (30 mL). The organic layer was separated, washed with brine (20 mL), dried over MgSO₄, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 10% 2 M ammonia in MeOH in DCM) provided (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2′-[1,4]oxazinan]-15′-one 13′,13′-dioxide (67 mg, 0.102 mmol, 60% yield) as a white solid. MS (ESI, +ve ion) m/z 654.2 (M+H)⁺.

Step 3: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-4″-benzyl-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one 13′,13′-dioxide

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-Chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one 13′,13′-dioxide (17 mg, 0.026 mmol), (bromomethyl)benzene (3.40 μl, 0.029 mmol), and triethylamine (7.95 μl, 0.057 mmol) were mixed in acetonitrile (0.25 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous NH₄Cl (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, washed with brine (10 mL), dried over MgSO₄, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 10% 2 M ammonia in MeOH in DCM) provided (1S,3′R,6′R,7′R,8′E,11′S,12′R)-4″-benzyl-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene-7′,2″-[1,4]oxazinan]-15′-one 13′,13′-dioxide (9 mg, 0.012 mmol, 47% yield) as a white solid. MS (ESI, +ve ion) m/z 744.3 (M+H)⁺.

Example 151 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Step 1: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-(2-methoxyethoxy)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜. 0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a solution of (1S,3′R,6′R,7′S,8E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (460 mg, 0.641 mmol) in tetrahydrofuran (8 mL) was added sodium hydride, 60% dispersion in mineral oil (679 mg, 19.24 mmol) in portions. After addition, the mixture was then stirred at room temperature under nitrogen for 10 min, then 2-bromoethyl methyl ether (1.809 mL, 19.24 mmol) was added. The resulting mixture was stirred at room temperature for 14 h. The mixture was quenched with saturated NH₄Cl (150 mL) and was extracted with EtOAc (2×200 mL). The combined organic extracts were dried over MgSO₄ and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc/heptane) provided (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-(2-methoxyethoxy)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (391 mg, 0.504 mmol, 79% yield) as a light yellow solid. MS (ESI, +ve ion) m/z 699.2, 755.3 (M+H)⁺.

Step 2: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide

A solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-(2-methoxyethoxy)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (391 mg, 0.504 mmol) in acetonitrile (10 mL) and water (2.500 mL) was added methyl iodide (0.313 mL, 5.04 mmol) and calcium carbonate (252 mg, 2.52 mmol). The resulting mixture was then stirred at 50° C. for 14 h. The mixture was quenched with saturated NH₄Cl and was extracted with EtOAc (2×100 mL). The combined organic extracts were then dried over MgSO₄ and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc/heptane) provided (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (233 mg, 0.340 mmol, 67.4% yield) as a light yellow solid. MS (ESI, +ve ion) m/z 685.3 (M+H)⁺.

Step 3: 2-methyl-2-propanyl (2R)-2-(((((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)amino)methyl)-1-piperidinecarboxylate

A solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (55 mg, 0.080 mmol) and (R)-tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (172 mg, 0.803 mmol) in 1,2-dichloroethane (0.8 mL) was stirred at room temperature for 14 h. Sodium triacetoxyborohydride (0.059 mL, 0.401 mmol) was added to the mixture and the mixture was then stirred at room temperature for 1 h. The mixture was diluted with MeOH (5 mL) and silica gel was added. The mixture was concentrated and dried in vacuo. The solid mixture was then purified by silica gel column chromatography (solid loading, 0% to 100% EtOAc/heptane) provided 2-methyl-2-propanyl (2R)-2-(((((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)amino)methyl)-1-piperidinecarboxylate (64 mg, 0.072 mmol, 90% yield) as a light yellow solid. MS (ESI, +ve ion) m/z 883.5 (M+H)⁺.

Step 4: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-7′-((((2R)-2-piperidinylmethyl)amino)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a solution of 2-methyl-2-propanyl (2R)-2-(((((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)amino)methyl)-1-piperidinecarboxylate (58 mg, 0.066 mmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.098 mL, 1.3 mmol). The resulting mixture was then stirred at room temperature for 2 h. The mixture was cooled to 0° C. and iPr₂Net (0.457 mL, 2.63 mmol) was added followed by 1,2-dibromoethane (0.023 mL, 0.263 mmol) and DMA (0.1 mL). The resulting mixture was then stirred at room temperature for 72 h and at 50° C. for 1 h. The mixture was concentrated in vacuo and chromatographic purification of the residue (silica gel, 0% to 100% EtOAc/heptane) provided (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-7′-((((2R)-2-piperidinylmethyl)amino)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide as a colorless oil, which was used in the next step. MS (ESI, +ve ion) m/z 783.3 (M+H)⁺.

Step 5: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-7′-((((2R)-2-piperidinylmethyl)amino)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (51.4 mg, 0.066 mmol) in N, N-dimethylacetamide (0.4 mL) was added iPr₂Net (0.057 mL, 0.328 mmol) and 1,2-dibromoethane (0.028 mL, 0.328 mmol). The resulting mixture was then stirred at room temperature for 14 h. Then, 1,2-dibromoethane (0.2 mL) was added and the mixture was stirred at room temperature for 14 h then at 55° C. for 72 h. The mixture was purified by silica gel column chromatography (0% to 10% MeOH/DCM) provided (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-methoxyethoxy)-11′,12′-dimethyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (17 mg, 0.021 mmol, 32.0% yield) as a light yellow solid. MS (ESI, +ve ion) m/z 809.2 (M+H)⁺.

Example 154 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(((9aR)-3-oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Step 1: 2-methyl-2-propanyl (2R)-2-(((((1S,3′R,6′R,7′R,8E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)amino)methyl)-1-piperidinecarboxylate

To a solution of (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (44 mg, 0.069 mmol) in 1,2-dichloroethane (1 mL) was added (R)-tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (147 mg, 0.686 mmol). The resulting mixture was then stirred at room temperature for 1 h. Then, sodium triacetoxyborohydride (73 mg, 0.343 mmol) was added in portions. After addition, the mixture was then stirred at room temperature for 3 d. The mixture was purified by silica gel column chromatography (0% to 20% MeOH/DCM) to provide 2-methyl-2-propanyl (2R)-2-(((((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)amino)methyl)-1-piperidinecarboxylate (57.6 mg, 0.069 mmol, 100% yield) as a light yellow solid, which was used in the next step. MS (ESI, +ve ion) m/z 839.4 (M+H)⁺.

Step 2: 2-methyl-2-propanyl (2R)-2-(((chloroacetyl)(((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)amino)methyl)-1-piperidinecarboxylate

To a solution of 2-methyl-2-propanyl (2R)-2-(((((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)amino)methyl)-1-piperidinecarboxylate (57.6 mg, 0.069 mmol) in dichloromethane (1.5 mL) at −78° C. under nitrogen was added chloroacetyl chloride (10.92 μL, 0.137 mmol) followed by iPr₂Net (0.036 mL, 0.206 mmol). After addition, the mixture was then stirred at −78° C. for 1.5 h. Chloroacetyl chloride (0.022 mL) was added and the mixture was stirred at −25° C. for 1 h and placed in a −20° C. freezer for 16 h. The mixture was quenched with MeOH (2 mL) and concentrated in vacuo. Chromatographic purification (silica gel, 0% to 100% EtOAc/heptane) provided 2-methyl-2-propanyl (2R)-2-(((chloroacetyl)(((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)amino)methyl)-1-piperidinecarboxylate (62.8 mg, 0.069 mmol, 100% yield) as a light yellow solid. MS (ESI, +ve ion) m/z 937.3, 939.2 (M+Na)⁺.

Step 3: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(((9aR)-3-oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a solution of 2-methyl-2-propanyl (2R)-2-(((chloroacetyl)(((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)amino)methyl)-1-piperidinecarboxylate (61.8 mg, 0.067 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.251 mL, 3.37 mmol). After addition, the mixture was then stirred at room temperature for 17 min. The mixture was cooled to −78° C. and iPrNEt (0.704 mL, 4.05 mmol) was added dropwise. After addition, the mixture was stirred at room temperature for 14 h. The mixture was purified by silica gel column chromatography (0% to 20% MeOH/DCM) followed by preparative HPLC (Phenomenex Gemini C18 column, 150×30 mm, 10% to 100% 0.1% TFA in MeCN/H₂O) provided a desired product in a solution of MeCN/H₂O 0.1% TFA. The pH was adjusted to 7 with buffer (KH₂PO₄/K₂HPO₄) and extracted with EtOAc (2×10 mL). The combined extracts were washed with brine, dried (Na₂SO₄), concentrated, and dried in vacuo to provide (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(((9aR)-3-oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (33 mg, 0.042 mmol, 62.8% yield) as an off white solid. MS (ESI, +ve ion) m/z 779.3 (M+H)⁺.

Examples 176 and 177 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-N,N, 11′,12′-tetramethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carboxamide 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-N,N,11′,12′-tetramethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carboxamide 13′,13′-dioxide

Step 1: (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-15′-oxo-7′-methyoxy-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carboxylic acid 13′,13′-dioxide

To a 15-mL round-bottomed flask was added (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-15′-oxo-7′-methoxy-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (18 mg, 0.028 mmol, a mixture of two epimers) and 2-methyl-2-butene (149 μL, 1.404 mmol) in tert-butanol (281 μL) and water (281 μL). Potassium phosphate monobasic (38.2 mg, 0.281 mmol) and sodium chlorite (25.4 mg, 0.281 mmol) was added to the solution. The solution was stirred at room temperature for 1 h. The reaction mixture was diluted with saturated Na₂SO₃ (5 mL) and extracted with DCM (3×10 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over MgSO₄. The solution was filtered and concentrated in vacuo to give an off-white solid. The material was used in the next step without further purification. MS (ESI, +ve ion) m/z 657.2 (M+H)⁺.

Step 2: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-N,N,11′,12′-tetramethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carboxamide 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-N,N, 11′,12′-tetramethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carboxamide 13′,13′-dioxide

To a 5-mL round-bottomed flask was added (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-15′-oxo-7′-methyoxy-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carboxylic acid 13′,13′-dioxide (13 mg, 0.020 mmol, a mixture of two epimers) and diethylamine (2 M in THF, 39.6 μL, 0.079 mmol) in DCM (396 μL). 1-Propanephosphonic acid cyclic anhydride (50 wt. % solution in ethyl acetate, 62.9 μL, 0.099 mmol) was added at room temperature. The solution was stirred at room temperature for 2 h. The reaction mixture was diluted with saturated NaHCO₃ (5 mL) and extracted with EtOAc (2×10 mL). The organic layer was concentrated. The crude material was further purified by prep-HPLC to give two products. The first peak collected was assigned to be Example 176 and the second peak was assigned to be Example 177. MS (ESI, +ve ion) m/z 684.2 (M+H)⁺ for both isomers.

Examples 193 and 213 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide and (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Step 1: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-7′-(HYDROXYMETHYL)-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE AND (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-7′-(HYDROXYMETHYL)-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE

To a stirred ice-cooled solution of (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′ [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (1.015 g, 1.700 mmol) and trimethylsulfonium iodide (0.364 g, 1.785 mmol) in dimethyl sulfoxide (4.0 mL) was dropwise added potassium tert-butoxide, 1.0 M solution in tetrahydrofuran (4.25 mL, 4.25 mmol) under argon. The resulting mixture was stirred in the ice bath for 5 min and at ambient temperature for 30 min. The crude reaction mixture was directly loaded onto a silica gel precolumn (25 g) previously covered with a layer of ammonium chloride and subjected to combi-flash column chromatography on a 24 g ISCO gold column eluting with 0% to 100% EtOAc/Hexanes followed by 5% to 20% MeOH/DCM to give an approximately 3:1 mixture of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide and (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (0.82 g, 1.3 mmol, 79% yield) as a white solid. MS (ESI, +ve ion) m/z 629.2 (M+1)⁺.

Step 2: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAENE]-7′-CARBALDEHYDE 13′,13′-DIOXIDE AND (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAENE]-7′-CARBALDEHYDE 13′,13′-DIOXIDE

To a stirred ice-cooled solution of a mixture of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide and (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (180 mg, 0.286 mmol) in DCM (5.0 mL) was added under argon Dess-Martin periodinane (121 mg, 0.286 mmol) in one portion as a solid. The resulting mixture was stirred under argon at 0° C. for 10 min and at ambient temperature for a period of 3 h. The crude mixture was directly loaded onto a silica gel precolumn (25 g) and subjected to combi-flash column chromatography on a 12 g ISCO gold column eluting with 0% to 20% MeOH/DCM to give 180 mg of an impure mixture of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide and (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide as an off-white solid. It was taken onto the next step without further purification. MS (ESI, +ve ion) m/z 627.2 (M+1)⁺.

Step 3: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-((9AS)-HEXAHYDROPYRAZINO[2,1-C][1,4]OXAZIN-8(1H)-YLMETHYL)-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE AND (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-CHLORO-7′-((9AS)-HEXAHYDROPYRAZINO [2,1-C][1,4]OXAZIN-8(1H)-YLMETHYL)-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE

The title compounds were prepared from a mixture of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide and (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide according to General Method 10. (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (Example 193) was the second eluting epimer off the silica gel column. MS (ESI, +ve ion) m/z 753.3 (M+1)⁺.

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (Example 213) was the first eluting epimer off the silica gel column. MS (ESI, +ve ion) m/z 753.3 (M+1)⁺.

Example 194 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-7′-(4-MORPHOLINYLMETHYL)-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE

Step 1: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-7′-(HYDROXYMETHYL)-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE

The title compound was obtained as a single stereoisomer from a silica gel column chromatography separation of an epimeric mixture of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide and (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide eluting with 1% to 20% MeOH/DCM. The title compound was the second eluting epimer off the silica gel column. MS (ESI, +ve ion) m/z 629.3 (M+1)⁺.

Step 2: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAENE]-7′-CARBALDEHYDE 13′,13′-DIOXIDE

The title compound was synthesized from (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide according to the protocol in Example 193 (Step 2). MS (ESI, +ve ion) m/z 627.4 (M+1)⁺.

Step 3: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-7′-(4-MORPHOLINYLMETHYL)-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE

The title compound was synthesized from (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide according to General Method 10. MS (ESI, +ve ion) m/z 698.5 (M+1)⁺.

Example 270 (4-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-METHOXY-11′,12′-DIMETHYL-13′,13′-DIOXIDO-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-7′-YL)METHYL)-1-PIPERAZINYL)ACETIC ACID

To a stirred solution of methyl (4-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)-1-piperazinyl)acetate (Example 269) (15 mg, 0.019 mmol) in MeOH (1.5 mL) and water (0.5 mL) was added lithium hydroxide hydrate (8.0 mg, 0.19 mmol). The resulting mixture was stirred at room temperature for 3 h. The residue was taken up in MeOH and subjected to preparative reverse-phase HPLC (Gemini™ Prep C18 10 μm column; Phenomenex, Torrance, Calif.; gradient elution of 20 to 90% MeCN in water, where both solvents contain 0.1% TFA, a 15-min gradient in a 24-min method) to give, after lyophilization, 11 mg of (4-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl)-1-piperazinyl)acetic acid as a white solid. MS (ESI, +ve ion) m/z 769.7 (M+1)⁺.

Example 276 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-(((9AS)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-METHOXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE OR (1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-(((9AR)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-METHOXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE

A solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(((9aS)-8-(3-(phenylsulfonyl)propanoyl)octahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(((9aR)-8-(3-(phenylsulfonyl)propanoyl)octahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (15 mg, 0.016 mmol) and 1,8-diazabicyclo-[5.4.0]undec-7-ene (0.15 mL, 1.0 mmol) in pyridine (0.30 mL) in a microwave reaction vessel was subjected to microwave irradiation for 50 min at 75° C. The crude mixture was taken up in MeOH and subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 10 μm column; Phenomenex, Torrance, Calif.; gradient elution of 20 to 90% MeCN in water, where both solvents contain 0.1% TFA, a 15-min gradient in a 24-min method) to give, after lyophilization, 7.5 mg of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-(((9AS)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-METHOXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE OR (1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-(((9AR)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-METHOXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE. MS (ESI, +ve ion) m/z 821.0 (M+1)⁺.

Example 345 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1H-1,2,3-triazol-1-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1H-1,2,3-triazol-1-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Step 1: (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-7′-methylidene-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

A solution of methyltriphenylphosphonium bromide (1.80 g, 5.0 mmol) in THF (15 mL) was cooled to 0° C. n-butyllithium solution (2.5 M in hexanes, 1.8 mL, 4.5 mmol) was added dropwise and it was stirred at 0° C. for 10 min. The bromide solution was added dropwise to a solution of (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (0.30 g, 0.50 mmol) in THF (6.0 mL) (cooled in ice bath) until the yellow color persisted. It was stirred at 0° C. for 12 min. The reaction mixture was added to stirred ice water (20 mL). It was acidified with 1 N HCl to pH 2-4. The organic phase was separated and the aqueous was extracted with EtOAc (50 mL). The organic phase was washed with brine and dried over magnesium sulfate. The filtrate was concentrated to give crude product. The compound was purified by medium pressure chromatography (silica, 0% to 50% EtOAc (+0.3% HOAc:Hexanes) to give (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-7′-methylidene-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (290 mg, 0.49 mmol, 97% yield). MS (ESI, +ve ion) m/z 595.2 (M+H)⁺.

Step 2: (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

The AD-Mix-alpha mixture (640 mg, 0.43 mmol) was dissolved in a 20 mL of a 1:1 mixture of tert-butanol (10.0 mL) and water (10.0 mL) and cooled to 0° C. The (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-7′-methylidene-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (255 mg, 0.428 mmol) was added and the reaction mixture was warmed slowly to room temperature overnight. Another 5.0 mL of t-BuOH was added to homogenize the mixture. The reaction was stirred overnight. Another 320 mg of AD-Mix-alpha mixture was added and the reaction was stirred for an additional 3 d. The reaction was quenched by adding 575 mg of sodium sulfite at 0° C. and stirring for 45 minutes. The mixture was then extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine (1×20 mL) and dried over sodium sulfate. The crude product was then purified by medium pressure chromatography (silica, 0% to 100% EtOAc (+0.3% HOAc):heptanes) to give (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (31 mg, 0.049 mmol, 12% yield). MS (ESI, +ve ion) m/z 629.2 (M+H)⁺.

Step 3: ((1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl methanesulfonate

(1S,3′R,6′R,8′E,11′S,12′R)-6-Chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (25.0 mg, 0.040 mmol) was dissolved in DCM (800 μL) and cooled to 0° C. Triethylamine (17 μL, 0.12 mmol) was added followed by mesyl chloride (6.50 μL, 0.083 mmol) addition and the reaction was stirred for 1.5 h. The reaction was then diluted with DCM (15 mL) and the mixture was washer with water (2×10 mL) and dried over sodium sulfate. The crude product was then purified by medium pressure chromatography (silica, 0% to 70% EtOAc (+0.3% HOAc):heptanes) to give ((1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl methanesulfonate. MS (ESI, +ve ion) m/z 707.2 (M+H)⁺.

Step 4: (1S,3′R,6′R,8′E,11′S,12′R)-7′-(azidomethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

((1S,3′R,6′R,8′E,11′S,12′R)-6-Chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)methyl methanesulfonate (10 mg, 0.014 mmol) was dissolved in 0.36 mL of a 5:1 DMF:water mixture. To the solution was added sodium azide (2.1 mg, 3.2 μmol). The mixture was heated to 70° C. and stirred overnight. The reaction was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate and the crude product was purified by medium pressure chromatography (silica, 0% to 60% EtOAc (+0.3% HOAc):heptanes) to give (1S,3′R,6′R,8′E,11′S,12′R)-7′-(azidomethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (2.1 mg, 3.2 μmol, 23% yield). MS (ESI, +ve ion) m/z 654.2 (M+H)⁺.

Step 5: (1S,3′R,6′R,8′E,11′S,12′R)-7′-(azidomethyl)-6-chloro-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

(1S,3′R,6′R,8′E,11′S,12′R)-7′-(Azidomethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (2.0 mg, 3.1 μmol) was dissolved in 2-methyltetrahydrofuran (1.0 mL) and sodium hydride (60% dispersion) (0.73 mg, 0.031 mmol) was added followed by methyl iodide (0.956 μL, 0.015 mmol). The reaction was then stirred overnight to completion. The reaction was quenched with dropwise addition of water and extracted with EtOAc. The organic layers were then washed with brine and dried over magnesium sulfate to give (1S,3′R,6′R,8′E,11′S,12′R)-7′-(azidomethyl)-6-chloro-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (3.0 mg) that was used directly in the next reaction without any further purification. MS (ESI, +ve ion) m/z 668.2 (M+H)⁺.

Step 6: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1H-1,2,3-triazol-1-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1H-1,2,3-triazol-1-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

(1S,3′R,6′R,8′E,11′S,12′R)-7′-(Azidomethyl)-6-chloro-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (20 mg, 0.030 mmol) was slurried in 3.0 mL of a 1:1:1 t-BuOH:water:DMF solution. To the solution was added copper (II) sulfate (2.9 mg, 0.018 mmol), (+)-sodium 1-ascorbate (12.0 mg, 0.061 mmol) and (trimethylsilyl)acetylene (65 μL, 0.46 mmol). The solution was then heated in a microwave reactor at 120° C. for 2 h. The reaction was then diluted with water and EtOAc. The mixture was extracted with EtOAc (2×25 mL). The combined organic layers were washed with 1 N lithium chloride solution (1×15 mL) and brine (1×15 mL) then dried over magnesium sulfate. The residue was then purified by medium pressure chromatography (silica, 25% to 100% EtOAc (+0.3% HOAc):heptanes) to give (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1H-1,2,3-triazol-1-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(1H-1,2,3-triazol-1-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide. MS (ESI, +ve ion) m/z 694.3 (M+H)⁺.

Example 348 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-7′-(2-methylpropoxy)-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Step 1: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-11′,12′-dimethyl-7′-((2-methyl-2-propen-1-yl)oxy)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0-19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

The reaction was performed following the procedure for general method 5, step 2. MS (ESI, +ve ion) m z 771.2 (M+H)⁺.

Step 2: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-11′,12′-dimethyl-7′-(2-methylpropoxy)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

The (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-11′,12′-dimethyl-7′-((2-methyl-2-propen-1-yl)oxy)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (200 mg, 0.26 mmol) was dissolved in EtOAc (5.0 mL) and platinum (IV) oxide (180 mg, 0.78 mmol) was added. The vessel was then pressurized to 40 psi with hydrogen and stirred for 3.5 h to completion. The black slurry was then filtered through a pad of Celite and washed with EtOAc. The filtrate was then concentrated to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-11′,12′-dimethyl-7′-(2-methylpropoxy)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (200 mg, 0.26 mmol, 100% yield). MS (ESI, +ve ion) m/z 773.2 (M+H)⁺.

Step 3: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-7′-(2-methylpropoxy)-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide

The reaction was performed following the procedure for general method 5, step 3. MS (ESI, +ve ion) m/z 683.3 (M+H)⁺.

Step 4: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-7′-(2-methylpropoxy)-7′-((4-(3-oxetanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

The reaction was performed following the procedure for general method 8. MS (ESI, +ve ion) m/z 809.2 (M+H)⁺.

Examples 362 and 363 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-((2S)-2-hydroxypropyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-((2R)-2-hydroxypropyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-Chloro-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-12′-yl)acetaldehyde (Example 360) (32 mg, 0.040 mmol) was dissolved in THF (2.0 mL) and cooled to 0° C. Methylmagnesium bromide (3.4 M in 2-MeTHF, 0.12 mL, 0.40 mmol) was added dropwise and stirred for 45 min. The reaction was quenched with saturated ammonium chloride solution (15 mL) and the mixture was extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (1×20 mL) and then dried over sodium sulfate. The mixture was then purified by preparatory SCF chromatography (4FBSA, 250 mm×21 mm column, Phenomenex, Torrance, Calif.; 28 g/minute MeOH (+20 mM NH₃)+42 g/minute CO₂ on Thar 200 SFC; outlet pressure=100 bar; temperature=40° C.; wavelength=220 nm; used 1.1 mL injections of 28 mg/3 mL (9.3 mg/mL) sample solution of MeOH (3 mL) to give (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-((2S)-2-hydroxypropyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-((2R)-2-hydroxypropyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (Example 362, first eluting isomer, t_(R)=3.19 minutes on analytical SFC; 4FBSA; 40% MeOH (+20 mM NH₃ in CO₂) with >99.5% de) (6.2 mg, 7.7 μmol, 19% yield). MS (ESI, +ve ion) m/z 809.4 (M+H)⁺. And (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-((2S)-2-hydroxypropyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-((2R)-2-hydroxypropyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (Example 363, second eluting isomer, t_(R)=6.49 minutes on analytical SFC; 4FBSA; 40% MeOH (+20 mM NH₃ in CO₂) with >99.5% de) (13 mg, 0.016 mmol, 39% yield). MS (ESI, +ve ion) m/z 809.4 (M+H)⁺.

Examples 364 and 366 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′-methyl-3,4-dihydro-2H,16′H-spiro[naphthalene-1,23′-[21]oxa[27]thia[1,15]diazapentacyclo[15.7.2.1˜12,15˜.0˜3,6˜.0˜20,25˜]heptacos a[8,17,19,25]tetraen]-16′-one 27′,27′-dioxide AND (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-12′-(2-chloroethyl)-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Step 1: 2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′-methyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-12′-yl)ethyl methanesulfonate

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-Chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-12′-(2-hydroxyethyl)-7′-methoxy-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (Example 346) (15 mg, 0.018 mmol) was dissolved in DCM (1.0 mL) and the Hunig's base (0.011 mL, 0.064 mmol) and mesyl chloride (3.7 μL, 0.048 mmol) were added. The reaction mixture was stirred for 1.5 h to near completion. The mixture was then diluted with DCM (20 mL) and water (15 mL). The layers were separated and the organic layer was dried over sodium sulfate. The filtrate was concentrated to dryness under vacuum to give 2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′-methyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-12′-yl)ethyl methanesulfonate (16 mg, 0.018 mmol, 100% yield) that was used directly in the next reaction. MS (ESI, +ve ion) m/z 875.3 (M+H)⁺.

Step 2: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′-methyl-3,4-dihydro-2H,16′H-spiro[naphthalene-1,23′-[21]oxa[27]thia[1,15]diazapentacyclo[15.7.2.1˜12,15˜.0˜3,6˜.0˜20,25˜]heptacos a[8,17,19,25]tetraen]-16′-one 27′,27′-dioxide AND (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-12′-(2-chloroethyl)-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-Chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′-methyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-12′-yl)ethyl methanesulfonate (16 mg, 0.018 mmol) was dissolved in acetonitrile (1.0 mL) and tetrabutylammonium difluoro-triphenylsilicate (59 mg, 0.11 mmol) was added. The reaction was then heated at 75° C. to completion. The reaction was then cooled to room temperature and then diluted with EtOAc (25 mL) and water (20 mL). The layers were separated and the organic layer was washed again with water (1×20 mL) and brine (1×20 mL) and dried over sodium sulfate. The crude product was then purified by medium pressure chromatography (silica, 0% to 100% (10% 2 M ammonia in MeOH):DCM) to give two products, (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′-methyl-3,4-dihydro-2H,16′H-spiro[naphthalene-1,23′-[21]oxa[27]thia[1,15]diazapentacyclo[15.7.2.1˜12,15˜.0˜3,6˜.0˜20,25˜]heptacos a[8,17,19,25]tetraen]-16′-one 27′,27′-dioxide (Example 364) (4.9 mg, 6.3 μmol, 34% yield), MS (ESI, +ve ion) m/z 779.3 (M+H)⁺ AND (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-12′-(2-chloroethyl)-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-methoxy-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (Example 366) (3.5 mg, 4.29 μmol, 23% yield), MS (ESI, +ve ion) m/z 815.3 (M+H)⁺.

Examples 358, 359, and 367 (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-(2-hydroxyethyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (Example 358) AND (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′-methyl-12′-(2-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)ethyl)-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (Example 359) AND (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-(2-(dimethylamino)ethyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (Example 367)

Step 1: (3R,4S)-1-HYDROXY-N,N-BIS(4-METHOXYBENZYL)-4-METHYL-6-HEPTENE-3-SULFONAMIDE

To a solution of (S)—N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-1-sulfonamide (2.8 g, 6.9 mmol) in THF (15 mL) was added n-butyllithium (2.5 M in hexanes, 3.1 mL, 7.6 mmol) at −78° C. dropwise. The mixture was stirred at −78° C. for 5 min, and ethylene oxide (2.5 M in THF, 5.6 mL, 14 mmol) was then added. The mixture was allowed to warm up to ambient temperature and stirred for 18 h. The mixture was quenched with saturated aqueous NH₄Cl, and extracted with EtOAc (2×). The organic layer was washed with brine, dried (MgSO₄), and filtered. The filtrate was concentrated and the resulting residue was chromatographed (silica gel, 20% to 60%, EtOAc/Hexane) to afford a diasteromeric mixture of the title compound. The mixture was then purified by preparatory SFC chromatography (ChiralPak IC-H 250 mm×30 mm column, Phenomenex, Torrance, Calif.; 35 g/minute MeOH+105 g/minute CO₂ on Thar 200 SFC; outlet pressure=100 bar; temperature=22° C.; wavelength=215 nm; used 1.0 mL injections of 25,000 mg/50 mL (500 mg/mL) sample solution of MeOH (50 mL) to provide (3R,4S)-1-hydroxy-N,N-bis(4-methoxybenzyl)-4-methyl-6-heptene-3-sulfonamide as the slower eluting isomer as a yellow liquid (t_(R)=2.51 minutes on analytical SFC; IC-H column; 25% MeOH in CO₂) with 100% de. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 7.24 (d, J=8.61 Hz, 4H), 6.90 (d, J=8.61 Hz, 4H), 5.62 (ddt, J=16.75, 10.20, 7.07, 7.07 Hz, 1H), 5.08 (s, 1H), 5.05 (br d, J=7.83 Hz, 1H), 4.39 (d, J=15.26 Hz, 2H), 4.23 (d, J=15.26 Hz, 2H), 3.83 (s, 6H), 3.66-3.81 (m, 2H), 3.00-3.16 (m, 1H), 1.97-2.23 (m, 3H), 1.79-1.96 (m, 3H), 1.06 (d, J=6.85 Hz, 3H). MS (ESI, +ve ion) m/z 470.2 (M+Na)⁺.

Step 2: (3R,4S)—N,N-bis(4-methoxybenzyl)-4-methyl-1-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)-6-heptene-3-sulfonamide

(3R,4S)-1-Hydroxy-N,N-bis(4-methoxybenzyl)-4-methylhept-6-ene-3-sulfonamide (6.4 g, 14 mmol) was dissolved in DMF (34 mL). Imidazole (1.7 g, 24 mmol) and tert-butyldiphenylsilyl chloride (6.3 mL, 24 mmol) were added and the mixture was stirred for 45 min. The reaction was then quenched with saturated ammonium chloride solution (150 mL) and extracted with EtOAc (1×300 mL). The layers were separated and the organic was washed (1×100 mL) with 1 N LiCl solution (1×100 mL), 1 N HCl solution and (1×100 mL) of brine and then dried over magnesium sulfate. The crude product was then purified by medium pressure chromatography (silica, 5% to 100% EtOAc:Heptanes) to give (3R,4S)—N,N-bis(4-methoxybenzyl)-4-methyl-1-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)-6-heptene-3-sulfonamide (9.70 g, 14.14 mmol, 98% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.67 (dt, J=1.5, 7.3 Hz, 4H), 7.47-7.35 (m, 6H), 7.16 (d, J=8.8 Hz, 4H), 6.79-6.78 (m, 1H), 6.81 (d, J=8.6 Hz, 3H), 5.56 (tdd, J=7.0, 10.1, 17.0 Hz, 1H), 4.97 (dd, J=1.8, 10.0 Hz, 1H), 4.91 (dd, J=1.6, 17.0 Hz, 1H), 4.31-4.10 (m, 4H), 3.84-3.80 (m, 1H), 3.78 (s, 6H), 3.77-3.72 (m, 1H), 3.09 (ddd, J=1.6, 4.2, 7.4 Hz, 1H), 2.22-2.07 (m, 2H), 1.98-1.79 (m, 3H), 1.07 (s, 9H), 1.02 (d, J=6.8 Hz, 3H). MS (ESI, +ve ion) m/z 708.3 (M+Na)⁺.

Step 3: (3R,4S)-4-methyl-1-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)-6-heptene-3-sulfonamide

To a 1000 mL flask cooled to 0° C., was added (3R,4S)—N,N-bis(4-methoxybenzyl)-4-methyl-1-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)-6-heptene-3-sulfonamide (9.4 g, 14 mmol), DCM (290 mL), anisole (7.5 mL, 69 mmol) and then trifluoroacetic acid (49 mL). The reaction was allowed to warm to room temperature overnight to completion. The reaction mixture was then concentrated on the rotovap to a volume of ˜25 mL. The crude product was then purified by medium pressure chromatography (silica, 10% to 50% EtOAc:heptanes) to give (3R,4S)-4-methyl-1-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)-6-heptene-3-sulfonamide (2.7 g, 6.1 mmol, 44% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.67 (ddd, J=1.5, 5.8, 7.2 Hz, 4H), 7.49-7.37 (m, 6H), 5.72 (tdd, J=6.9, 10.1, 17.0 Hz, 1H), 5.06-4.94 (m, 2H), 4.41 (br s, 2H), 3.93-3.80 (m, 2H), 3.23-3.16 (m, 1H), 2.46 (m, 1H), 2.13-2.06 (m, 1H), 2.05-2.01 (m, 1H), 1.91 (dtd, J=3.7, 7.1, 14.7 Hz, 2H), 1.07 (s, 9H), 1.02 (d, J=7.0 Hz, 3H). MS (ESI, +ve ion) m/z 468.2 (M+Na)⁺.

Step 4: (3 S)-6′-chloro-5-(((1R,2R)-2-((1S)-1-hydroxy-2-propen-1-yl)cyclobutyl)methyl)-N-(((3R,4S)-4-methyl-1-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)-6-hepten-3-yl)sulfonyl)-3′,4,4′,5-tetrahydro-2′H-spiro[1,5-benzoxazepine-3,1′-naphthalene]-7-carboxamide

The reaction was performed following the procedure for general method 1 (R¹=H). MS (ESI, +ve ion) m/z 895.3 (M+H)⁺.

Step 5: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′-methyl-12′-(2-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

The reaction was performed following the procedure for general method 1 (R¹=H). MS (ESI, +ve ion) m/z 867.3 (M+H)⁺.

Step 6: (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′-methyl-12′-(2-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)ethyl)-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide

The reaction was performed following the procedure for general method 1 (R¹=H). MS (ESI, +ve ion) m/z 865.3 (M+H)⁺.

Step 7: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′-methyl-12′-(2-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

The reaction was performed following the procedure for general method 3 (R⁴=Me). MS (ESI, +ve ion) m/z 911.4 (M+H)⁺.

Step 8: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′-methyl-12′-(2-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)ethyl)-5′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide

The reaction was performed following the procedure for general method 3 (R⁴=Me). MS (ESI, +ve ion) m/z 909.3 (M+H)⁺.

Step 9: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′-methyl-12′-(2-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)ethyl)-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (Example 359)

The reaction was performed following the procedure for general method 8. MS (ESI, +ve ion) m/z 1033.3 (M+H)⁺.

Step 10: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-(2-hydroxyethyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (Example 358)

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-Chloro-7′-methoxy-11′-methyl-12′-(2-(((2-methyl-2-propanyl)(diphenyl)silyl)oxy)ethyl)-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (Example 359) (38 mg, 0.037 mmol) was dissolved in THF (1.0 mL). Tetrabutylammonium fluoride (1.0 M in THF, 1.1 mL, 1.1 mmol) was then added and the reaction was stirred for 24 h to completion. The reaction mixture was then diluted with DCM and then loaded directly on a column to purify by medium pressure chromatography (silica, 0% to 100% (hold) (10% 2 M ammonia in MeOH:DCM):DCM) to give product that was contaminated with tetrabutylammonium fluoride. This material was then diluted with water (50 mL) and EtOAc (20 mL). The layers were then separated and the organic layer was then washed again with water (1×50 mL) to remove the residual tetrabutylammonium fluoride. The organic layer was then extracted with brine (1×15 mL) and dried over sodium sulfate. The slurry was filtered and the filtrate was concentrated to give (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-(2-hydroxyethyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (Example 358) (150 mg, 0.18 mmol, 61% yield). MS (ESI, +ve ion) m/z 795.3 (M+H)⁺.

Step 11: 2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-12′-yl)ethyl methanesulfonate

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-Chloro-12′-(2-hydroxyethyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (Example 358) (50 mg, 0.063 mmol) was dissolved in DCM (3.0 mL) and the Hunig's Base (66 μL, 0.38 mmol) and mesyl chloride (21 μL, 0.26 mmol) were added. The reaction mixture was stirred for 1.5 h to completion. The mixture was then diluted with DCM (20 mL) and water (25 mL). The layers were separated and the organic layer was washed again with water (25 mL) and then was dried over sodium sulfate. The filtrate was concentrated to dryness under vacuum to give 2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-12′-yl)ethyl methanesulfonate (63 mg). MS (ESI, +ve ion) m/z 873.3 (M+H)⁺.

Step 12: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-(2-(dimethylamino)ethyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (Example 367)

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-Chloro-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-12′-yl)ethyl methanesulfonate (30 mg, 0.34 mmol), dimethylamine (2 M in THF, 0.17 mL, 0.34 mmol), potassium carbonate (95 mg, 0.69 mmol) and a catalytic amount of potassium iodide was dissolved in acetonitrile (1.0 mL) in a vial and sealed with a pressure cap. The reaction mixture was then heated to 65° C. for 40 min to completion. The reaction was then diluted with DCM and filtered through a fine glass frit. The filtrate was then concentrated and the residue was then purified by preparatory SFC chromatography (Kromasil Cyano 250 mm×21 mm column 17.5 g/minute MeOH (+20 mM ammonia)+52.5 g/minute CO₂ on Thar 200 SFC; outlet pressure=100 bar; temperature=22° C.; wavelength=215 nm; used 1.0 mL injections of 31 mg/4 mL (7.8 mg/mL) sample solution of MeOH (4 mL) to give (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-12′-(2-(dimethylamino)ethyl)-7′-methoxy-11′-methyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (Example 367) (4.7 mg, 5.7 mmol, 17% yield) as the slower eluting peak (t_(R)=2.90 minutes on analytical SFC; Kromasil Cyano column 25% MeOH in CO₂) with 97.8% purity. MS (ESI, +ve ion) m/z 822.3 (M+H)⁺.

Examples 399 and 400 (1S,3′R,6′R,7′R,9″S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,9a″S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one 13′,13′-dioxide

Step 1: (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide

A glass microwave reaction vessel was charged with (1S,3′R,6′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,2″-oxiran]-15′-one 13′,13′-dioxide (0.300 g, 0.489 mmol) and 3(R)-hydroxymethylmorpholine (0.650 g, 5.55 mmol; Matrix Sci., Elgin, S.C.). Ethanol (3 mL) and triethylamine (1.8 mL, 12.9 mmol) were added, the reaction mixture was sealed under argon, and heated in an Initiator microwave reactor at 90° C. for a total of 27 h. The reaction was heated at 90° C. in the microwave for another 16 h. The reaction mixture was purified by reverse-phase HPLC (Gilson; Gemini-NX 10 μm, C18, AXIA, 100×50 mm column) eluting with 0.1% TFA-H₂O:0.1% TFA CH₃CN (9:1-1:9). The fractions containing the desired product were combined and partitioned between pH 7 buffer (1 M K₂HPO₄/KH₂PO₄)/EtOAc. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were washed with brine, dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to give a mixture of (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide and (1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide (177 mg, 50%) as a white crystalline solid.

Step 2: (1S,3′R,6′R,7′R,9a″S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,9a″S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one 13′,13′-dioxide

To a room temperature mixture of (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide and (1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((3R)-3-(hydroxymethyl)-4-morpholinyl)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide (0.136 g, 0.186 mmol) in tetrahydrofuran (4 mL) was added sodium hydride, 60% dispersion in mineral oil (0.050 g, 1.250 mmol) and the reaction was stirred for 30 min. To the reaction was added p-toluenesulfonic anhydride (0.250 g, 0.766 mmol) and the reaction was stirred for 5.5 h. To the reaction was added sodium hydride, 60% dispersion in mineral oil (0.050 g, 1.250 mmol) and the reaction was stirred overnight. To the reaction was added p-toluenesulfonic anhydride (0.180 g) and the reaction was stirred for 24 h. To the reaction was added sodium hydride, 60% dispersion in mineral oil (0.050 g, 1.25 mmol) and the reaction was stirred for another 24 h. The reaction was quenched with pH 7 buffer (1 M K₂HPO₄/KH₂PO₄) and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine and the filtrate was purified by reverse-phase HPLC (Gilson; Gemini-NX 10 μm, C18, AXIA, 100×50 mm column) eluting with 0.1% TFA-H₂O:0.1% TFA CH₃CN (9:1→1:9). The fractions containing the desired product were combined and partitioned between pH 7 buffer (1 M K₂HPO₄/KH₂PO₄)/EtOAc. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were washed with brine, dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to give 118 mg (89%) of a white solid. The material was purified by achiral SFC chromatography to give (1S,3′R,6′R,7′R,9a″S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,9a″S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one 13′,13′-dioxide (10 mg, 8%, first eluted peak) as a white crystalline solid. m/z (ESI, +ve ion) 712.7 (M+1)⁺. A second eluting compound was isolated as (1S,3′R,6′R,7′R,9a″S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,9a″S,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4,6″,7″,9″,9a″-hexahydro-1″H,2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,3″-[1,4]oxazino[3,4-c][1,4]oxazin]-15′-one 13′,13′-dioxide (12 mg, 9%, second eluted peak) as a white crystalline solid. (ESI, +ve ion) m/z 712.6 (M+1)⁺.

Example 405 (1S,3′R,6′R,7′S,10′S,11'S)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-hydroxy-10′,11′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide

A vial was charged with (1S,3′R,6′R,7′S,8′E,10′S,11'S)-6-chloro-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-7′-hydroxy-10′,11′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (0.012 g, 0.016 mmol) and platinum (IV) oxide (0.4 mg, 1.6 μmol). Ethanol (2 mL) and methanol (0.3 mL) were added. The reaction was flushed with nitrogen for 5 min then evacuated/backfilled with hydrogen three times. The reaction was stirred under 20 psi hydrogen at room temperature overnight. The reaction was flushed with nitrogen. Methanol (5 mL) and DCM (5 mL) were added. The reaction was flushed with nitrogen then evacuated/backfilled with hydrogen three times. The reaction was stirred under 20 psi hydrogen at room temperature for 24 h. The reaction was flushed with nitrogen and filtered through celite rinsing with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by silica gel flash chromatography using a gradient of 0% to 10% MeOH in DCM to afford the title compound (0.007 g, 9 μmol, 58% yield). MS (ESI, +ve ion) m/z 755.2 (M+H)⁺.

Example 466 (1S,3′R,6′R,7′R,11′S,12′R)-6-CHLORO-11′,12′-DIMETHYL-4′-(METHYLSULFONYL)-3,4-DIHYDRO-2H,15′H-DISPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIENE-7′,2″-[1,4]OXAZINAN]-15′-ONE 13′,13′-DIOXIDE AND (1S,3′R,6′R,7′S,11′S,12′R)-6-CHLORO-11′,12′-DIMETHYL-4″-(METHYLSULFONYL)-3,4-DIHYDRO-2H,15′H-DISPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIENE-7′,2″-[1,4]OXAZINAN]-15′-ONE 13′,13′-DIOXIDE

To a stirred solution of (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((2-hydroxyethyl)amino)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-7′-(((2-hydroxyethyl)amino)methyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide (Example 452) (34 mg, 0.043 mmol) in THF (1.5 mL) in a microwave reaction vessel was added at room temperature, diisopropylethylamine (0.075 mL, 0.431 mmol) under argon followed by methanesulfonic anhydride (37.6 mg, 0.216 mmol). The resulting mixture was stirred at room temperature for 5 min during which the color of the mixture changed from colorless to light greenish yellow. The vessel was capped and subjected to microwave reaction irradiation (3 h at 70° C.). 4-(Dimethylamino)pyridine (15.81 mg, 0.129 mmol) was then added followed by more methanesulfonic anhydride (18 mg, 0.11 mmol). The vessel was sealed and again subjected to microwave irradiation (4 h at 70° C.). The volatiles were removed and the concentrate was dissolved in DMSO and purified by preparative reverse-phase HPLC (Gemini™ Prep C18 5 μm column; Phenomenex, Torrance, Calif.; gradient elution of 30% to 95% MeCN in water, where both solvents contain 0.1% TFA, 25 min method) to provide, after lyophilization, 4.0 mg of (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-4″-(methylsulfonyl)-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24 ]triene-7′,2″-[1,4]oxazinan]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-11′,12′-dimethyl-4″-(methylsulfonyl)-3,4-dihydro-2H,15′H-dispiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-7′,2″-[1,4]oxazinan]-15′-one 13′,13′-dioxide as a white solid. MS (ESI, +ve ion) m/z 734.2 (M+1)⁺.

Examples 499 and 500 METHYL 3-((9AR)-8-(((1S,3′R,6′R,7′R,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-13′,13′-DIOXIDO-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIEN]-7′-YL)METHYL)OCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)PROPANOATE AND METHYL 3-((9AR)-8-(((1S,3′R,6′R,7′S,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-13′,13′-DIOXIDO-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIEN]-7′-YL)METHYL)OCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)PROPANOATE AND METHYL 3-((9AS)-8-(((1S,3′R,6′R,7′R,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-13′,13′-DIOXIDO-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIEN]-7′-YL)METHYL)OCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)PROPANOATE AND METHYL 3-((9AS)-8-(((1S,3′R,6′R,7′S,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-13′,13′-DIOXIDO-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIEN]-7′-YL)METHYL)OCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)PROPANOATE (Example 499) AND (1S,3′R,6′R,7′R,11′S,12′R)-7′-(((9AR)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIEN]-15′-ONE 13′,13′-DIOXIDE AND (1S,3′R,6′R,7′R,11′S,12′R)-7′-(((9AS)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIEN]-15′-ONE 13′,13′-DIOXIDE AND (1S,3′R,6′R,7′S,11′S,12′R)-7′-(((9AR)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIEN]-15′-ONE 13′,13′-DIOXIDE AND (1S,3′R,6′R,7′S,11′S,12′R)-7′-(((9AS)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIEN]-15′-ONE 13′,13′-DIOXIDE (Example 500)

To a stirred solution of (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((9aR)-octahydro-2H-pyrazino[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((9aS)-octahydro-2H-pyrazino[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide (1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((9aR)-octahydro-2H-pyrazino[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo [14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide (1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((9aS)-octahydro-2H-pyrazino[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide (Example 479) (0.15 g, 0.199 mmol) and diisopropylethylamine (1.5 mL, 8.62 mmol) in DCM (10 mL) was added at room temperature acrylic acid n-hydroxysuccinimide ester (0.303 g, 1.789 mmol) in one portion as a solid. The resulting mixture was stirred at room temperature for 3 h. MeOH (8 mL) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 20 min before concentrated in vacuo. The crude residue was directly loaded onto a silica gel precolumn (25 g) and subjected to combi-flash column chromatography on a 12 g ISCO gold column eluting with 1% to 20% MeOH/DCM to give 30 mg of impure product mixture, which was subjected to preparative reverse-phase HPLC (Gemini™ Prep C18 10 μm column; Phenomenex, Torrance, Calif.; gradient elution of 20% to 90% MeCN in water, where both solvents contain 0.1% TFA, a 15-min gradient in a 24-min method) to give, after lyophilization, 18.5 mg of METHYL 3-((9AR)-8-(((1S,3′R,6′R,7′R,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-13′,13′-DIOXIDO-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIEN]-7′-YL)METHYL)OCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)PROPANOATE AND METHYL 3-((9AR)-8-(((1S,3′R,6′R,7′S,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-13′,13′-DIOXIDO-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO [14.7.2.0˜3,6˜.0˜19,24˜]PENTACOSA[16,18,24]TRIEN]-7′-YL)METHYL)OCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)PROPANOATE AND METHYL 3-((9AS)-8-(((1S,3′R,6′R,7′R,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-13′,13′-DIOXIDO-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIEN]-7′-YL)METHYL)OCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)PROPANOATE AND METHYL 3-((9AS)-8-(((1S,3′R,6′R,7′S,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-13′,13′-DIOXIDO-15′-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIEN]-7′-YL)METHYL)OCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)PROPANOATE (EXAMPLE 499) in an approximately 1-to-1-to-1-to-1 epimeric mixture. MS (ESI, +ve ion) m/z 841.0 (M+1)⁺. In addition, (1S,3′R,6′R,7′R,11′S,12′R)-7′-(((9AR)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIEN]-15′-ONE 13′,13′-DIOXIDE AND (1S,3′R,6′R,7′R,11′S,12′R)-7′-(((9AS)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIEN]-15′-ONE 13′,13′-DIOXIDE AND (1S,3′R,6′R,7′S,11′S,12′R)-7′-(((9AR)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIEN]-15′-ONE 13′,13′-DIOXIDE AND (1S,3′R,6′R,7′S,11′S,12′R)-7′-(((9AS)-8-ACRYLOYLOCTAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-2-YL)METHYL)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIEN]-15′-ONE 13′,13′-DIOXIDE (EXAMPLE 500) was isolated as a white solid in a 1-to-1-to-1-to-1 epimeric mixture. MS (ESI, +ve ion) m/z 808.8 (M+1)⁺.

Example 507 (1S,3′R,6′R,7′S,11′S,12′R)-7′-(aminomethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,11′S,12′R)-7′-(aminomethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide

(1S,3′R,6′R,7′S,11′S,12′R)-7′-(Azidomethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24]pentacosa[16,18,24]tri en]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,11′S,12′R)-7′-(azidomethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24]pentacosa[16,18,24]tri en]-15′-one 13′,13′-dioxide (Example 506) (36.0 mg, 0.055 mmol) was dissolved in ethyl acetate (5.0 mL) and platinum(IV) oxide (2.49 mg, 11.0 μmol) was added. The reaction vessel was filled with hydrogen to 15 psi and stirred vigorously for 2.5 h. MeOH (1.5 mL) was added and the reaction vessel was again filled with hydrogen (15 psi) and stirred overnight. The slurry was filtered and the precipitate was washed with DMSO to ensure that no product was remaining on the catalyst. The filtrate was concentrated. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 μm, C18, 100 Å, 150×30 mm, 0.1% TFA in CH₃CN/H₂O, gradient 20% to 85% over 30 min to provide (1S,3′R,6′R,7′S,11′S,12′R)-7′-(aminomethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,11′S,12′R)-7′-(aminomethyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide (32 mg, 0.037 mmol, 68% yield) as a di-TFA salt. MS (ESI, +ve ion) m/z 630.2 (M+H)⁺.

Examples 517 and 518 (1S,3′R,6′R,7′R,11′S,12′R)-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide

A reaction vessel was charged with platinum (IV) oxide (18.6 mg, 0.082 mmol), then placed in a Biotage Endeavor and treated with a solution of (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (128 mg) in EtOAc (3 mL). The vessel was purged with Ar (3×), then pressurized to 200 psi with H₂ and stirred (250 RPM) at 80° C. for 20 h. The vessel was cooled to room temperature and purged with Ar (3×), then filtered through a celite pad that was rinsed liberally with EtOAc. The filtrate was concentrated in vacuo and purified by reverse-phase preparative HPLC (Shimadzu) on a Phenomenex Luna column (5 μm, C18, 110 Å, Axia, 150 mm×21.2 mm) eluting at 30 mL/min with a linear gradient of 25% to 100% MeCN (0.1% TFA) in water (0.1% TFA) over 20 min. The desired fractions were poured into 10% Na₂CO₃ and extracted with DCM (2×5 mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo to afford (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide (Example 518) (32.8 mg, 0.040 mmol, 13% yield) as a white solid. MS (ESI, +ve ion) m/z 827.2 (M+H)⁺. In addition, (1S,3′R,6′R,7′R,11′S,12′R)-7′-ethoxy-7′-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide (Example 517) was isolated as an earlier eluting peak (12.9 mg, 0.016 mmol, 6% yield) as a white solid. MS (ESI, +ve ion) m/z 793.3 (M+H)⁺.

Example 519 (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-(((3R)-3-methyl-4-(2-propanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide

Step 1: (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-7′-(hydroxymethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide

A reaction vessel was charged with sulfided Pt on carbon (5% wt %, 54.2 mg, 0.295 mmol), then placed in the Biotage Endeavor and treated with a solution of (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-ethoxy-7′-(hydroxymethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide [derived from methods analogous to General Method 3, steps 1-2 using (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide] (207 mg, 0.295 mmol) in EtOAc (3.25 mL). The vessel was purged with Ar (3×), then pressurized to 200 psi with H₂ and stirred (250 RPM) at 80° C. for 20 h. The vessel was cooled to room temperature and purged with Ar (3×), then filtered through a celite pad that was rinsed liberally with EtOAc. The filtrate was concentrated in vacuo to afford (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-7′-(hydroxymethyl)-12′-(2-methoxyethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide (196 mg, 0.279 mmol, 94% yield) as a white solid. MS (ESI, +ve ion) m/z 703.3 (M+H)⁺.

Step 2: (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene]-7′-carbaldehyde 13′,13′-dioxide

To an ice bath cooled solution of (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-7′-(hydroxymethyl)-12′-(2-methoxy ethyl)-11′-methyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide (161 mg, 0.229 mmol) in DCM (10 mL) was added 0.3 M Dess-Martin Periodinane in DCM (1.0 mL, 0.300 mmol) dropwise over 2 min. After 1.5 h, LC-MS suggests about 60% conversion, the reaction was treated with another 0.9 mL of 0.3 M Dess-Martin Periodinane in DCM dropwise over 1 min. After a further 2.5 h, LC-MS suggests complete conversion. The reaction was treated with 5 mL of saturated sodium bisulfite and stirred for 20 min. The reaction was poured into water (15 mL) and the organic layer separated. The aqeuous layer was extracted with DCM (1×5 mL). The combined organic layers were concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (Gold, 12 g), eluting with 0% to 25% EtOAc in heptanes, to afford (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene]-7′-carbaldehyde 13′,13′-dioxide (105 mg, 0.150 mmol, 65.4% yield) as a white solid. MS (ESI, +ve ion) m/z 701.2 (M+H)⁺.

Step 3: (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-(((3R)-3-methyl-4-(2-propanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide

To a round bottom flask was charged the TFA salt of (R)-1-isopropyl-2-methylpiperazine (68.2 mg, 0.285 mmol) and (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene]-7′-carbaldehyde 13′,13′-dioxide (50 mg, 0.071 mmol) in DCE (2 mL) and N,N-diisopropylethylamine (0.1 mL, 0.574 mmol). After 1.5 h, the solution was treated with sodium triacetoxyborohydride (6 mg). After a further 3 h, the reaction was treated with more sodium triacetoxyborohydride (7 mg). After a further 16 h, the reaction was again treated with sodium triacetoxy borohydride (6 mg). The reaction was monitored by LC-MS and sodium triacetoxyborohydride added in 5-10 mg portions until reaction was judged complete. After a further 24 h, the reaction was diluted with DCE (3 mL). After 4 d, the reaction was treated with acetic acid (12 μL, 0.208 mmol). After a further 24 h, more acetic acid (18 μL) was added. After a further 24 h, the reaction was treated with another 30 mg of amine. After a further 96 h, the reaction was treated with larger portions of sodium triacetoxyborohydride to drive reaction to desired product or the alcohol resulting from reduced aldehyde. LC-MS suggests no further progress, the reaction was quenched with water and the aqeuous layer extracted with DCM (2×10 mL). The combined DCM layers were concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (Gold, 12 g), eluting with 0% to 80% EtOAc:EtOH (3:1) in heptanes, to afford (1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-ethoxy-12′-(2-methoxyethyl)-11′-methyl-7′-(((3R)-3-methyl-4-(2-propanyl)-1-piperazinyl)methyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide (24.2 mg, 0.029 mmol, 41.0% yield) as a white solid. MS (ESI, +ve ion) m/z 827.4 (M+H)⁺.

Table 1 lists compounds prepared by the General Methods outlined in the present specification

TABLE 1 Examples Prepared by the General Methods MS Example Starting General Data Number Materials Method Product Structure Product Name (M + 1)⁺ 22

5, 12

(1S,3′R,6′R,7′S,8′E,11′S, 12′S)-6-chloro-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-12′- (2-methoxyethyl)-11′- methyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3, 6~.0~19,24]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 812.4 23

 

5, 12

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 12′-(2-methoxyethyl)-11′- methyl-7′-((4-(3-oxetanyl)- 1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3, 6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 812.2 24

 

5, 12

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 12′-(2-methoxyethyl)-11′- methyl-7′-((4-(1- methylethyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3, 6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 798.2 25

 

5, 12

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 12′-(2-methoxyethyl)-7′- ((4-(2-methoxy-1- (methoxymethyl)ethyl)-1- piperazinyl)methyl)-11′- methyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3, 6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 858.4 26

 

5, 12

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 12′-(2-methoxyethyl)-11′- methyl-7′-((4-((5-methyl- 1,2,4-oxadiazol-3- yl)methyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3, 6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 852.4 27

 

5, 12

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 7′-((4-(2-methoxy-1,1- dimethylethyl)-1- piperazinyl)methyl)-12′-(2- methoxyethyl)-11′-methyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3, 6~.0~19,24~]pentacosa[8,16, 18,24]tetraen]-15′-one 13′,13′-dioxide 842.4 28

 

1 (R¹ = H), 5, 8

(1S,3′R,6′R,7′S,8′E,12′R)- 6-chloro-12′-ethyl-7′- ((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.2 29

 

 

1 (R¹ = H), 5, 8

(1S,3′R,6′R,7′S,8′E,12′R)- 6-chloro-12′-ethyl-7′- methoxy-7′-((9aR)- octahydro-2H-pyrido[1,2- a]pyrazin-2-ylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 765.2 30

 

 

1 (R¹ = H), 5, 8

(1S,3′R,6′R,7′R,8′E,12′R)- 6-chloro-12′-ethyl-7′- ((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24-]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.2 31

 

 

1 (R¹ = H), 5, 8

(1S,3′R,6′R,7′S,8′E,12′R)- 6-chloro-12′-ethyl-7′- methoxy-7′-((4-methyl-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen-15′-one 13′,13′-dioxide 725.2 32

 

 

1 (R¹ = H), 5, 8

(1S,3′R,6′R,7′R,8′E,12′R)- 6-chloro-12′-ethyl-7′- methoxy-7′-((9aR)- octahydro-2H-pyrido[1,2- a]pyrazin-2-ylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- 20]oxa[13]thia[1,14] diazatetracyclo]14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 765.2 35

 

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- ((methyl(2-(4- morpholinyl)ethyl)amino) methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24-]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 769.2 36

 

5, 13

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-(((2-(4- morpholinyl)ethyl)amino) methyl)-3,4-dihydro- 2H,15′H- spiro[naphtlalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 755.2 37

 

5, 13

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((methyl(2-(4- morpholinyl)ethyl)amino) methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 769.2 38

 

 

2, 5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (cyclobutylmethyl)-7′- ((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-11′- methyl-3,4-dihydro- 2H,15′H- spiroοnaphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 821.2 39

 

 

2, 5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-12′- (cyclobutylmethyl)-7′- ((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-11′- methyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 821.2 40

 

 

2, 5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-12′- (cyclobutylmethyl)-7′- methoxy-11′-methyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 819.2 41

 

 

2, 5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-12′- (cyclobutylmethyl)-7′- methoxy-11′-methyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H, spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 819.2 42

 

 

1 (R¹ = H), 5, 8

(1S,3′R,6′R,7′R,8′E,12′R)- 6-chloro-7′-ethoxy-12′- ethyl-7′-((9aR)-octahydro- 2H-pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 779.2 43

 

 

1 (R¹ = H), 5, 8

(1S,3′R,6′R,7′S,8′E,12′R)- 6-chloro-7′-ethoxy-12′- ethyl-7′-((9aR)-octahydro- 2H-pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 779.2 44

 

 

2, 5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-12′- (cyclobutylmethyl)-7′- ethoxy-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′-methyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 835.2 45

 

 

2, 5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-12′- (cyclobutylmethyl)-7′- ethoxy-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′-methyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen-15′-one 13′,13′-dioxide 835.2 46

 

3, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′,12′- dimethyl-7′-(2-propen-1- yloxy)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 793.2 47

 

3, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′,12′- dimethyl-7′-(1- methylethoxy)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 795.2 48

 

3, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-7′-butoxy-6-chloro- 7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′,12′- dimethyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 809.2 49

 

3, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′,12′- dimethyl-1-7′-(2,2,2 trifluoroethoxy)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 835.2 50

 

3, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′,12′- dimethyl-7'-(2,2,2- trifluoroethoxy)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 835.2 51

 

3, 10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-11′,12′- dimethyl-7′-(1- methylethoxy)-7′-(((3R)-3- methyl-4-(1-methylethyl)- 1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 795.2 52

 

5, 12

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-(4- morpholinylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 712.2 53

 

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-(4-morpholinylmethyl)- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 712.3 54

 

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-7′-((4-(2- methoxyethyl)-3-oxo-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 783.2 55

 

5, 12

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 7′-((4-(2-methoxyethyl)-3- oxo-1-piperazinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 783.2 56

 

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.3 57

 

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((9aR)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.3 58

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((9aR)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.3 59

 

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((3- (dimethylamino)-3-methyl- 1-azetidinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 739.4 60

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((3- (dimethylamino)-3-methyl- 1-azetidinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 739.3 61

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-7′-((4-(2- methoxyethyl)-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 769.4 62

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((4-methyl-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 725.5 63

 

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((8aS)-3- oxotetrahydro[1,3]oxazolo [3,4-a]pyrazin-7(1H)- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.3 64

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-(((8aS)-3- oxotetrahydro[1,3]oxazolo [3,4-a]pyrazin-7(1H)- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.3 65

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- ((methylamino)methyl)- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 656.4 66

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- ((dimethylamino)methyl)- 7′-methoxy-11′,12′- dimethyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 670.3 67

 

5, 10

1- (((1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-7′-yl)methyl)- 3-methyl-3- azetidinecarbonitrile 721.3 68

 

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((5- fluoro-3,6-dihydro-1(2H)- pyridinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 726.3 69

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- ((dimethylamino)methyl)- 7′-methoxy-11′,12′- dimethyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 670.2 70

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((methylamino)methyl)- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 656.2 71

10

1- (((1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-7′-yl)methyl)- 3-methyl-3- azetidinecarbonitrile 721.3 72

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((4-(1,3-thiazol-4- ylmethyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3.6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 808.2 73

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((4-(2- (methylsulfonyl)ethyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 817.2 74

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-(1-piperidinylmethyl)- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 710.3 75

 

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-(1- piperidinylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 710.2 76

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-7′-(1- azetidinylmethyl)-6-chloro- 7′-methoxy-11′,12′- dimethyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 682.3 77

 

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(1- azetidinylmethyl)-6-chloro- 7′-methoxy-11′,12′- dimethyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 682.3 78

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((9aS)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 765.8 79

 

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- ((9aS)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl]-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 765.8 80

 

5, 10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((8aR)- hexahydropyrrolo[1,2- a]pyrazin-2(1H)-ylmethyl)- 7′-methoxy-11′,12′- dimethyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]tlhia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((8aS)- hexahydropyrrolo[1,2- a]pyrazin-2(1H)-ylmethyl)- 7′-methoxy-11′,12′- dimethyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 751.8 81

 

5, 9

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11,12′-dimethyl-7′-((4-(2- (methylsulfonyl)ethyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0-3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13,13′-dioxide 818.0 82

 

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-(((3aR,6aS)-5- methylhexahydropyrrolo[3, 4-c]pyrrol-2(1H)- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 751.2 83

 

9

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((8aR)- hexahydropyrrolo[1,2- a]pyrazin-2(1H)-ylmethyl)- 7′-methoxy-11′,12′- dimethyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa [8,16,18, 24]tetraen]-15′-one 13′,13′- dioxide|(1S,3′R,6′R,7′R,8′E, 11′S,12′R)-6-chloro-7′- ((8aS)- hexahydropyrrolo[1,2- a]pyrazin-2(1H)-ylmethyl)- 7′-methoxy-11,12′- dimethyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 751.2 84

 

9

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((3-(4-morpholinyl)-1- azetidinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[l,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.2 85

 

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((4-(4-morpholinyl)-1- piperidinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 795.9 86

 

8

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- ((4aR,8aS)-octahydro- 2(1H)- isoquinolinylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24-]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′- dioxide AND (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- ((4aS,8aR)-octahydro- 2(1H)- isoquinolinylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′- dioxide 764.8 87

 

8

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((10aR)- octahydropyrazino[1,2- a]azepin-2(1H)-ylmethyl)- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((10aS)- octahydropyrazino[1,2- a]azepin-2(1H)-ylmethyl)- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 779.8 88

 

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((4- ethyl-1- piperazinyl)methyl)-7′- methoxy-11,12 -dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8.16.18, 24]tetraen]-15′-one 13′,13′-dioxide 739.8 89

 

8

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((4aR,8aS)-octahydro- 2(1H)- isoquinolinylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7,2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((4aS,8aR)-octahydro- 2(1H)- isoquinolinylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 764.2 90

 

8

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((4aS,8aR)-octahydro- 2(1H)- isoquinolinylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((4aR,8aS)-octahydro- 2(1H)- isoquinolinylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 764.2 91

 

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((4- cyclopropyl-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7,2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 751.8 92

 

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((4- cyclobutyl-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 765.8 93

 

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((4-(2,2,2- trifluoroethyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 794.0 94

 

9

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-7′-((3-((2- methoxyethyl)(methyl) amino)-1-azetidinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7,2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 769.8 95

 

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((4-(2,2- difluoroethyl)-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7,2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 775.8 96

 

9

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((4-(2- fluoroethyl)-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 757.2 97

 

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((4-propyl-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 753.3 98

 

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 11′,12′-dimethyl-7′-((4- propyl-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.3 101

5, 9

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′,12′- dimethyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 781.8 102

 

 

1, 5, 9

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-12′-benzyl-6-chloro- 7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-11′- methyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′S)-12′-benzyl-6-chloro- 7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-11′- melhyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 844.0 103

 

 

1, 5, 9

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-12′-benzyl-6-chloro- 7′-((9aS)- hexahydropyrazino[2,1- c] [1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-11′- methyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S, 12′S)-12′-benzyl-6-chloro- 7′-((9aS)- hexahydropyrazino[2,1- c] [1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-11′- methyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14,7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 844.0 104

 

 

1, 5, 8

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-12′-benzyl-6-chloro- 7′-methoxy-11′-methyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′S)-12′-benzyl-6-chloro- 7′-methoxy-11′-methyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19.24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 841.2 106

 

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 11′,12′-dimethyl-7′-((4-(3- oxetanyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 781.2 107

 

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 11′,12′-dimethyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 779.3 108

 

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 11′,12′-dimethyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 779.3 109

 

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 11′,12′-dimethyl-7′-(2- oxa-7-azaspiro[3.5]non-7- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 766.3 110

 

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4- (dimethylamino)-1- piperidinyl)methyl)-7′- ethoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.3 111

 

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 7′-((4-(2-methoxy-1- (methoxymethyl)ethyl)-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 827.2 112

 

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 7′-((4-ethyl-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 753.3 113

 

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 7′-((4-methoxy-1- piperidinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 754.8 114

 

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 11′,12′-dimethyl-7′-((4-(1- methylethyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.3 115

 

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 11′12′-dimethyl-7′-((4-(1- methylethyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.8 116

 

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 7′-((4-(2-methoxy-1- (methoxymethyl)ethyl)-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 828.0 117

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 7′-((4-methoxy-1- piperidinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 740.7 118

 

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4- (dimethylamino)-1- piperidinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 753.7 119

 

5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 11′,12′-dimethyl-7′-(1- oxa-7-azaspiro[3.5]non-7- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 766.8 120

 

5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-(1- oxa-7-azaspiro[3.5]non-7- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 752.8 121

 

5, 8

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)- 2,2- dioxidohexahydropyrazino [2,1-c][1,4]thiazin-8(1H)- yl)methyl)-7′-ethoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR 1S′,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)- 2,2- dioxidohexahydropyrazino [2,1-c][1,4]thiazin-8(1H)- yl)methyl)-7′-ethoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 830.0 122

 

5, 8

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)- 2,2- dioxidohexahydropyrazino [2.1-c][1,4]thiazin-8(1H)- yl)methyl)-7′-ethoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[l,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR 1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)- 2,2- dioxidohexahydropyrazino [2.1-c][1,4]thiazin-8(1H)- yl)methyl)-7′-ethoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 830.0 123

 

5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 7′-((4-(2-methoxyethyl)-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 783.9 129

 

See Example 138 (Step 1)

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- hydroxy-7′-(((2- hydroxyethyl)(methyl)amino) methyl)-11′,12′- dimethyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 686.3 130

See Example 138 (Step 2)

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-4″,11′,12′- trimethyl-3,4-dhydro- 2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraene-7′,2″- [1,4]oxazinan]-15′-one 13′,13′-dioxide 668.3 131

 

See Example 138 (Step 1 with Net₃ due to HCl salt, Step 2)

(1S,3′R,6′R,7′R,8′E,9a″R, 11′S,12′R)-6-chloro- 11′,12′-dimethyl- 3,4,6″,7″,9″,9a″- hexahydro-1″H,2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19.24~]pentacosa[8,16,18, 24]tetraene-7′,3″- [1,4]oxazino[3,4- c][1,4]oxazin]-15′-one 13′,13′-dioxide 710.2 132

 

See Example 138 (Steps 1-2)

 

(1S,3′R,6′R,7′R,8′E,9a″R, 11′S,12′R-6-chloro- 8″,11′,12′-trimethyl- 1″,3,4,6″,7″,8″,9″,9a″- octahydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraene-7′,3″- pyrazino[2,1- c][1,4]oxazin]-15′-one 13′,13′-dioxide Or (1S,3′R,6′R,7′R,8′E,9a″S, 11′S,12′R)-6-chloro- 8″,11′,12′-trimethyl- l″,3,4,6″,7″,8″,9″,9a″- octahydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraene-7′,3″- pyrazino[2,1- c][1,4]oxazin]-15′-one 13′,13′-dioxide 723.3 133

 

See Example 138 (Steps 1-2)

 

(1S,3′R,6′R,7′R,8′E,9a″R, 11′S,12′R-6-chloro- 8″,11′,12′-trimethyl- 1″,3,4,6″,7″,8″,9″,9a″- octahydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraene-7′,3″- pyrazino[2,1- c][1,4]oxazin]-15′-one 13′,13′-dioxide Or (1S,3′R,6′R,7′R,8′E,9a″S, 11′S,12′R)-6-chloro- 8″,11′,12′-trimethyl- l″,3,4,6″,7″,8″,9″,9a″- octahydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraene-7′,3″- pyrazino[2,1- c][1,4]oxazin]-15′-one 13′,13′-dioxide 723.3 134

 

See Example 138 (Steps 1-2)

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-11′,12′- dimethyl-3,4-dihydro- 2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraene-7',2″- [1,4]oxazinan]-15′-one 13′,13′-dioxide 654.2 135

 

 

See Example 138 (Steps 1-3)

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-11,12′- dimethyl-4″-(tetrahydro- 2H-pyran-4-ylmethyl)-3,4- dihydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraene-7',2″- [1,4]oxazinan]-15′-one 13′,13′-dioxide 752.3 136

 

 

See Example 138 (Steps 1-3)

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-11′,12′- dimethyl-4″-(4- pyridinylmethyl)-3,4- dihydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraene-7′,2″- [1,4]oxazinan]-15′-one 13′,13′-dioxide 745.3 137

 

 

See Example 138 (Steps 1-3)

(1S,3′R,6′R,7′R,8′E,11′S, l2′R)-6-chloro-11′,12′- dimethyl-4″-(3- pyridinylmethyl)-3,4- dihydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraene-7′,2″- [1,4]oxazinan]-15′-one 13′,13′-dioxide 745.3 139

 

 

See Example 138 (Steps 1-3)

(1S,3′R,6′R,7′R,8′E,11′S, l2′R)-6-chloro-4″- (cyclohexylmethyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15’H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraene-7′,2″- [1,4]oxazinan]-15′-one 13′,13′-dioxide 750.3 140

 

8

(1S,3′R,6′R,7′R,8′E,11′S, l2′R)-6-chloro-7′- methoxsy-11′,12′-dimethyl- 7′-(((9aS)-4- oxohexahydropyrazino [2,1-c][1,4]oxazin-8(1H)- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 781.2 141

 

8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aS)-4- oxohexahydropyrazino [2,1-c][1,4]oxazin-8(1H)- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 781.2 142

 

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-(((3S,9aS)-3-methyl-4- oxohexahydropyrazino [2.1-c][1,4]oxazin-8(1H)- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 795.3 143

 

8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((3S,9aS)-3-methyl-4- oxohexahydropyrazino [2.1-c][1,4]oxazin-8(1H)- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 795.2 144

 

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-(((3R,9aS)-3-methyl-4- oxohexahydropyrazino [2,1-c][1,4]oxazin-8(1H)- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 795.3 145

 

8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((3S,9aS)-3- methylhexahydropyrazino [2,1-c][1,4]oxazin-8(1H)- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 781.4 146

 

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-(((3S,9aS)-3- methylhexahydropyrazino [2,1-c][1,4]oxazin-8(1H)- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 781.2 147

 

8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((3R,9aS)-3- methylhexahydropyrazino [2,1-c][1,4]oxazin-8(1H)- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 781.2 148

 

8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(3,4- dihydro-2(1H)- isoquinolinylmethyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 758.3 149

 

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-(((9aR)-4-oxooctahydro- 2H-pyrido[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 779.3 150

 

8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aR)-4-oxooctahydro- 2H-pyrido[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15]H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 779.3 152

 

 

 

See example 151

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(2- methoxyethoxy)-11′,12′- dimethyl-7′-((9aR)- octahydro-2H-pyrido[1,2- a]pyrazin-2-ylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 809.2 153

 

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((4-(2,2- dimethylpropyl)-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 781.3 155

 

 

5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (cyclopropylmethoxy)- 11′,12′-dimethyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 805.3 156

 

 

2, 5, 8

(1S,3′R,6′R,7′S,8′E,10′S, 11′S)-6-chloro-7′-((9aS)- hexahydropyrazino[2,1 - c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy- 10′, 11′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767   157

 

 

2, 5, 8

(1S,3′R,6′R,7′R,8′E,10′S, 11′S)-6-chloro-7′-((9aS)- hexahydropyrazino[2,1- c] [1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy- 10′,11′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.2 158

 

 

2, 5, 8

(1S,3′R,6′R,7′S,8′E,10′S, 11′S)-6-chloro-7′-methoxy- 10′,11′-dimethyl-7′-((4-(3- oxetanyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.2 159

 

 

2, 5, 8

(1S,3′R,6′R,7′R,8′E,10′S, 11′S)-6-chloro-7′- methoxy-10′,11′-dimethyl- 7′-((4-(3-oxetanyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.2 160

 

 

2, 5, 8

(1S,3′R,6′R,7′R,8′E,10′S, 11′S)-6-chloro-7′- methoxy-10′,11′-dimethyl- 7′-((4-methyl-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 725.2 161

 

 

2, 5, 8

(1S,3′R,6′R,7′R,8′E,10′S, 11′S)-6-chloro-7′- methoxy-10′11′-dimethyl- 7′-((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 765.2 162

 

 

2, 5, 8

(1S,3′R,6′R,7′S,8′E,10′S, 11′S)-6-chloro-7′-((3- (dimethylamino)-3-methyl- 1-azetidinyl)methyl)-7′- methoxy-10′,11′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 739.2 163

 

 

2, 5, 8

(1S,3′R,6′R,7′S,8′E,10′S, 11′S)-6-chloro-7′-methoxy- 10′,11′-dimethyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 765.2 164

 

 

2, 5 (Step 1), 8

(1S,3′R,6′R,7′S,8′E,10′S, 11′S)-6-chloro-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-hydroxy- 10′,11′-dimethyl-3,4- dihydro-2H,15′H spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 753.2 165

 

 

2 (Step 1), 5, 8

(1S,3′R,6′R,7′R,8′E,10′S, 11′S)-6-chloro-7′-hydroxy- 10′,11′-dimethyl-7′-((4-(3- oxetanyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 753.2 166

 

 

2, 5, 8

(1S,3′R,6′R,7′R,8′E,10′S, 11′S)-6-chloro-7′-ethoxy- 10′,11′-dimethyl-7′-((4-(3- oxetanyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 781.2 167

 

 

2, 5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′S)-6-chloro-7′- methoxy-12′- (methoxymethyl)-11′- methyl-7′-((4-(3-oxetanyl)- 1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 797.2 168

 

 

2, 5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′S)-6-chloro-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-12′- (methoxymethyl)-11′- methyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 797.2 169

 

 

2, 5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′S)-6-chloro-7′- methoxy-12′- (methoxymethyl)-11′- methyl-7′-((9aR)- octahydro-2H-pyrido[1,2- a]pyrazin-2-ylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 795.2 170

 

 

2, 5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′S)-6-chloro-7′-methoxy- 12′-(methoxymethyl)-11′- methyl-7′-((4-(3-oxetanyl)- 1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 797.2 171

 

 

2, 5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′S)-6-chloro-7′-ethoxy- 7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-12′- (methoxymethyl)-11′- methyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 811.2 172

 

 

2, 5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′S)-6-chloro-7′-methoxy- 7′-((4-(2-methoxy-1- (methoxymethyl)ethyl)-1- piperazinyl)methyl)-12′- (methoxymethyl)-11′- methyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 843.2 173

 

 

2, 5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′S)-6-chloro-7′-methoxy- 12′-(methoxymethyl)-11′- methyl-7′-((4-(1- methylethyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 783.4 174

 

 

2, 5, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′S)-7′-((4-tert-butyl-1- piperazinyl)methyl)-6- chloro-7′-methoxy-12′- (methoxymethyl)-11′- methyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 797.2 175

 

 

2, 5, 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′S)-6-chloro-7′-ethoxy- 12′-(methoxymethyl)-11′- methyl-7′-((4-(3-oxetanyl)- 1-piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 811.2 178

 

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-12′-(2- methoxyethyl)-11′-methyl- 7′-((4-methyl-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 769.2 179

 

5, 10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-12′- (2-methoxyethyl)-11′- methyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 811.2 180

 

5, 12

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 12′-(2-methoxyethyl)-11′- methyl-7′-((4-methyl-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 769.2 181

 

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-12′-(2- methoxyethyl)-11′-methyl- 7′-((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 809.0 182

 

5, 12

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 12′-(2-methoxyethyl)-11′- methyl-7′-((9aR)- octahydro-2H-pyrido[1,2- a]pyrazin-2-ylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 809.2 184

 

 

1, 5, 11

(1S,3′R,6′R,7′R,8′E,11′S, 12′S)-6-chloro-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-12′- (methoxymethyl)-11′- methyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 797.2 185

 

5, 11

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 768.2 186

 

5, 11

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′12′-dimethyl- 7′-((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 766.2 187

 

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-12′-(2- methoxyethyl)-11′-methyl- 7′-((4-(3-oxetanyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 811.2 188

 

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-12′-(2- methoxyethyl)-11′-methyl- 7′-((4-(1-methylethyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 797.2 189

 

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-7′-((4-tert-butyl-1- piperazinyl)methyl)-6- chloro-7′-methoxy-12′-(2- methoxyethyl)-11′-methyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 811.2 190

 

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-7′-((4-tert-butyl-1- piperazinyl)methyl)-6- chloro-7′-ethoxy-12′-(2- methoxyethyl)-11′-methyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 825.2 191

 

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-12′-(2- methoxyethyl)-1 l′-methyl- 7′-(((3R,5S)-3,4,5- trimethyl-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 797.2 192

 

12

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-12′-(2- methoxyethyl)-11′-methyl- 7′-((4-(3-methyl-3- oxetanyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 825.2 195

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 7′-((4-(2-methoxyethyl)-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 769.2 196

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′12′-dimethyl-7′-((4- methyl-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 725.3 197

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 765.3 198

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(2,5- dioxa-8-azaspiro[3,5]non- 8-ylmethyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22'- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 754.4 199

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 7′-(((2R)-2- (methoxymethyl)-4- morpholinyl)methyl)- 11,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 756.3 200

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(6,7- dihydroisoxazolo[4,3- c]pyridin-5(4H)-ylmethyl)- 7′-methoxy-11′,12′- dimethyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22'- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 749.3 201

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(5,6- dihydroimidazo[1,2- a]pyrazin-7(8H)-ylmethyl)- 7′-methoxy-11′,12′- dimethyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 748.2 202

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((2,2- dioxido-2-thia-6- azaspiro[3,3]hept-6- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 772.3 203

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-(2- oxa-6-azaspiro[3.3]hept-6- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 724.3 204

 

10

tert-butyl 6- (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-7′yl)methyl)- 2,6-diazaspiro[3.3]heptane- 2-carboxylate 823.3 205

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11],12]-dimethyl-7′- (1,4,6,7-tetrahydro-5H- [1,2,3]triazolo[4,5- c]pyridin-5-ylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 749.3 206

 

10 (with in situ oxetane hydrolysis)

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-((3,3- bis(hydroxymethyl)-1- azetidinyl)methyl)-6- chloro-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 742.3 207

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(6,7- dihydro[1,2,3]triazolo[1,5- a]pyrazin-5(4H)-ylmethyl)- 7′-methoxy-11′,12′- dimethyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 749.5 208

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-(6- oxa-1-azaspiro[3.3]hept-1- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 724.4 209

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(6,7- dihydro[1,3]thiazolo[5,4- c]pyridin-5(4H)-ylmethyl)- 7′-methoxy-11′,12′- dimethyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 765.5 210

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aR)-8- methyloctahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aS)-8-methyloctahydro- 2H-pyrazino[1,2-a]pyrazin- 2-yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 780.5 211

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(5,8- dihydropyrido[3,4- d]pyrimidin-7(6H)- ylmethyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 760.3 212

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 7′- ((methoxy(methyl)amino) methyl)-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 686.5 214

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9aS)-8- acetyloctahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9aR)-8- acetyloctahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′- methoxy-11′, 12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 808.3 215

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)- 2,2- dioxidohexahydropyrazino [2,1-c][1,4]thiazin-8(1H)- yl)methyl)-7′-methoxy- 11′,12′,-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)- 2,2- dioxidohexahydropyrazino [2,1-c][1,4]thiazin-8(1H)- yl)methyl)-7′-methoxy- 11′,12′,-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 815.3 216

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aR)-8- methyloctahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′12′-dimethyl-7′- (((9aS)-8-methyloctahydro- 2H-pyrazino[1,2-a]pyrazin- 2-yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 780.5 217

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aR)-8- methyloctahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aR)-8- methyloctahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 780.5 218

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9aR)-8- acetyloctahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′- methoxy-11′12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22'- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-7′-(((9aR)-8- acetyloctahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′- methoxy-11′12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22'- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 808.3 219

 

10

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)-2,2- dioxidohexahydropyrazino [2,1-c][1,4]thiazin-8(1H)- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)-2,2- dioxidohexahydropyrazino [2,1-c][1,4]thiazin-8(1H)- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 815.2 220

 

10

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)- 2,2- dioxidohexahydropyrazino [2,1-c][1,4]thiazin-8(1H)- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)- 2,2- dioxidohexahydropyrazino [2,1-c][1,4]thiazin-8(1H)- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 815.2 221

 

10

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)- 2,2- dioxidohexahydropyrazino [2,1-c][1,4]thiazin-8(1H)- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)- 2,2- dioxidohexahydropyrazino [2,1-c][1,4]thiazin-8(1H)- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 815.2 222

 

8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(7,8- dihydropyrido[4,3- d]pyrimidin-6(5H)- ylmethyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 760.3 223

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(7,8- dihydropyrido[4,3- d]pyrimidin-6(5H)- ylmethyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 760.2 224

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((2,2- dioxido-2 -thia-6- azaspiro[3.3]hept-6- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 772.0 225

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9aS)-8- acetyloctahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9aS)-8- acetyloctahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 808.3 226

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9aS)-8- acetyloctahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9aS)-8- acetyloctahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 808.3 227

 

10

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aR)-8- (methylsulfonyl)octahydro- 2H-pyrazino[1,2-a]pyrazin- 2-yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aR)-8- (methylsulfonyl)octahydro- 2H-pyrazino[1,2-a]pyrazin- 2-yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 844.3 228

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aR)-8- (methylsulfonyl)octahydro- 2H-pyrazino[1,2-a]pyrazin- 2-yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aS)-8- (methylsulfonyl)octahydro- 2H-pyrazino[1,2-a]pyrazin- 2-yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 844.0 229

 

10

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-7′-(((9aS)-8- acetyloctahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-7′-(((9aR)-8- acetyloctahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 808.2 230

 

10

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-7′-(((9aS)-8- acetyloctahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-7′-(((9aR)-8- acetyloctahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 808.2 231

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)- 2,2- dioxidohexahydropyrazino [2,1-c][1,4]thiazin-8(1H)- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)- 2,2- dioxidohexahydropyrazino [2,1-c][1,4]thiazin-8(1H)- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 815.1 232

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)- 2,2- dioxidohexahydropyrazino [2,1-c][1,4]thiazin-8(1H)- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)- 2,2- dioxidohexahydropyrazino [2,1-c][1,4]thiazin-8(1H)- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 815.1 233

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aR)-8-(3- (phenylsulfonyl)propanoyl) octahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aS)-8-(3- (phenylsulfonyl)propanoyl) octahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 963.7 234

 

Example 276

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9aR)-8- acryloyloctahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9aS)-8- acryloyloctahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-6-chloro-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 820.3 235

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aR)-8-(1- methylethyl)octahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aS)-8-(1- methylethyl)octahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 828.0 236

 

10

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-hydroxy- 11′12′-dimethyl-7′-((9aR)- octahydro-2H-pyrido[1,2- a]pyrazin-2-ylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-hydroxy- 11′12′-dimethyl-7′-((9aR)- octahydro-2H-pyrido[1,2- a]pyrazin-2-ylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 751.4 237

 

10

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-(((9aS)-8- (methylsulfonyl)octahydro- 2H-pyrazino[1,2-a]pyrazin- 2-yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-(((9aR)-8- (methylsulfonyl)octahydro- 2H-pyrazino[1,2-a]pyrazin- 2-yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 844.2 238

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′12′-dimethyl- 7′-(((9aS)-8- (methylsulfonyl)octahydro- 2H-pyrazino[1,2-a]pyrazin- 2-yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′12′-dimethyl- 7′-(((9aS)-8- (methylsulfonyl)octahydro- 2H-pyrazino[1,2-a]pyrazin- 2-yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 844.2 239

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4-(1- methylethyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 753.7 240

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aS)-8-(1- methylethyl)octahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aR)-8-(1- methylethyl)octahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 809.0 241

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aS)-8-(1- methylethyl)octahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aR)-8-(1- methylethyl)octahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 809.0 242

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-hydroxy- 11′,12′-dimethyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl- 7′-((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 751.4 243

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-hydroxy- 11′,12′,-dimethyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-hydroxy- 11′,12′,-dimethyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 751.4 244

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aS)-8- (methylsulfonyl)octahydro- 2H-pyrazino[1,2-a]pyrazin- 2-yl)methyl)-3,4-dihydro- 2H,15’H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12’-dimethyl-7’- (((9aR)-8- (methylsulfonyl)octahydro- 2H-pyrazino[1,2-a]pyrazin- 2-yl)methyl)-3,4-dihydro- 2H,15’H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 844.3 245

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aS)-8- (methylsulfonyl)octahydro- 2H-pyrazino[1,2-a]pyrazin- 2-yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aR)-8- (methylsulfonyl)octahydro- 2H-pyrazino[1,2-a]pyrazin- 2-yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 844.3 246

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 7′-((4-(methoxyacetyl)-1- piperazinyl)methyl)- 11′12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 783.2 247

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4-ethyl- 1-piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 739.3 248

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4- (2,2,2-trifluoroethyl)-1- piperaziny)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 793.2 249

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-((acetyl-1- piperazinyl)methyl)-6- chloro-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 753.3 250

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4-(3 - oxetanyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.3 251

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4- phenyl-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 787.2 252

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12-dimethyl-7 ’ -((4-(2- pyridinyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15’H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 788.8 253

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4-(3- pyridinyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 788.8 254

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4-(4- pyridinyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 788.8 255

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4- (1,3-thiazol-2-yl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 794.8 256

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4-(2- pyrimidinyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 789.9 257

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4-(2- pyrazinyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 789.0 258

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7’-((3-(4- morpholinyl)-1- azetidinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.8 259

 

10

4- (((1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-7′-yl)methyl)- N,N-dimethyl-1- piperazinecarboxamide 782.9 260

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 7′-((3-((2- methoxyethyl)(methyl)amino)- 1-azetidinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 769.8 261

 

10

ethyl (4- (((1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-7′-yl)methyl)- 1-piperazinyl)acetate 797.0 262

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4- (tetrahydro-2H-pyran-4- yl)-1-piperazinyl)methyl)- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 796.0 263

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4-(4- morpholinyl)-1- piperidinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 796.0 264

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-(3- oxa-9-azaspiro[5.5]undec- 9-ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 780.8 265

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-(2- oxa-8-azaspiro[4.5]dec-8- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 766.2 266

 

10

methyl 4- (((1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihvdro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-7′-yl)methyl)- 1-piperazinecarboxylate 769.2 267

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-(2- oxa-7-azaspiro[3.5]non-7- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 752.8 268

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimeftyl-7′-((4-(3- methyl-3-oxetanyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 781.8 269

 

10

methyl (4- (((1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-7′-yl)methyl- 1-piperazinyl)acetate 783.8 271

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7’-((4- ((4R)-2-oxotetrahydro-2H- pyran-4-yl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7’-((4- ((4S)-2-oxotetrahydro-2H- pyran-4-yl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 810.0 272

 

10

3-(4- (((1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′, 12′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-7′-yl)methyl)- 1-piperazinyl)-3- oxetanecarbonitrile 792.8 273

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)-8,8- difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)-8,8- difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 801.9 274

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aR)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 783.9

AND (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aS)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide

AND (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8S,9aR)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide

AND (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8S,9aS)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 275

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4- ((3R)-tetrahydro-3- furanyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4- ((3S)-tetrahydro-3- furanyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 781.8 277

 

See example 276

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9AR)-8- ACRYLOYLOCTAHYDRO- 2H-PYRAZINO[1,2- A]PYRAZIN-2- YL)METHYL)-6- CHLORO-7′-METHOXY- 11′,12′-DIMETHYL-3,4- DIHYDRO-2H,15′H- SPIRO[NAPHTHALENE- 1,22′- [20]OXA[13]THIA[1,14] DIAZATETRACYCLO [14.7.2.0~3,6~.0~19,24~] PENTACOSA[8,16,18,24] TETRAEN]-15′-ONE 13′,13′- DIOXIDE OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-(((9AR)-8- ACRYLOYLOCTAHYDRO- 2H-PYRAZINO[1,2- A]PYRAZIN-2- YL)METHYL)-6- CHLORO-7′-METHOXY- 11′,12′-DIMETHYL-3,4- DIHYDRO-2H,15′H- SPIRO[NAPHTHALENE- 1,22′- [20]OXA[13]THIA[1,14] DIAZATETRACYCLO [14.7.2.0~3,6~.0~19,24~] PENTACOSA[8,16,18,24] TETRAEN]-15′-ONE 13′,13′- DIOXIDE 821.0 278

 

Aqueous hydrolysis of lactone

 

(3R)-3-(4- (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-7′-yl)methyl)- 1-piperazinyl)-5- hyddroxypentanoic acid AND (3S)-3-(4- (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-7′-yl)methyl)- 1-piperazinyl)-5- hyddroxypentanoic acid 828.0 279

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((3-(1,1- dioxido-4- thiomorpholinyl)-1- azetidinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 815.1 280

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-((4-(1-acetyl-3- azetidinyl)-1- piperazinyl)methyl)-6- chloro-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 808.2 281

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4- cyclobutyl-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 765.3 282

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4-(1- methyl-3-azetidinyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 780.2 283

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aR)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2 yl)methyl)-7′-methoxy 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aS)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2 yl)methyl)-7′-methoxy 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 783.9

 

OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8S,9aR)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2 yl)methyl)-7′-methoxy 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aS)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2 yl)methyl)-7′-methoxy 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 284

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aR)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aS)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 783.9

 

OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8S,9aR)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide Or (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- (((8S,9aS)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 285

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4- ((3S)-tetrahydro-3- furanyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4- ((3R)-tetrahydro-3- furanyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 781.3 286

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4- ((3S)-tetrahydro-3- furanyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4- ((3R)-tetrahydro-3- furanyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 781.3 287

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 7′-((4-(2-methoxy-1- (methoxymethyl)ethyl)-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 814.0 288

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)- 8,8-difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)- 8,8-difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 801.9 289

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)- 8,8-difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)- 8,8-difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 801.9 290

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy 11′,12′-dimethyl-7′-((3- methyl-2-oxo-1-oxa-3,8- diazaspiro[4.5]dec-8- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 795.9 291

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((7- methyl-6-oxo-5-oxa-2,7- diazaspiro[3.4]oct-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.8 292

 

10

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)-8,8- difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)-8,8- difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 801.9 293

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aR)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 783.9

AND (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aS)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide

AND (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8S,9aR)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide

AND (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8S,9aS)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 294

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7- (((9aS)-8-(3- (phenylsulfonyl)propanoyl) octahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7- (((9aR)-8-(3- (phenylsulfonyl)propanoyl) octahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 962.2 295

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aS)-8-(3- (phenylsulfonyl)propanoyl) octahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- (((9aR)-8-(3- (phenylsulfonyl)propanoyl) octahydro-2H- pyrazino[1,2-a]pyrazin-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 962.2 296

 

10 (in situ hydrolysis of boronate ester)

(2-acetyl-4-(4- (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-7′-yl)methyl- 1- piperazinyl)phenyl)boronic acid 873.2 297

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 7′-((4-(2-methoxy-1,1- dimethylethyl)-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 797.2 298

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)- 8,8-difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)- 8,8-difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 801.9 299

 

10

 

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(((9aS)- 8,8-difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-(((9aR)- 8,8-difluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 801.9 300

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4-(2- hydroxyethyl)-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 755.2 301

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-((4-butyl-1- piperazinyl)methyl)-6- chloro-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,l5′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.3 302

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 7′-((4-(3-methoxypropyl)- 1-piperazinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 783.2 303

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4-(2- ethoxyethyl)-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 783.3 304

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-7′-((4-(2- methoxy-1- (methoxymethyl)ethyl)-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 813.2 305

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4-(5- pyrimidinyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 789.9 306

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4-(2,2- difluoroethyl)-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 775.8 307

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-7′-((4-tert-butyl-1- piperazinyl)methyl)-6- chloro-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.8 308

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-((4-(bis(2- methoxyethyl)amino)-1- piperidinyl)methyl)-6- chloro-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 842.1 309

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4-(1,3- dioxolan-2-ylmethyl)-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 797.9 310

 

10 (with in situ oxetane hydrolysis)

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4-(3- hydroxy-2- (hydroxymethyl)propyl)-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 800.0 311

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 11′,12′-dimethyl-7′-((4-(3- methyl-3-oxetanyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 796.0 312

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-((4-bis(2- methoxyethyl)amino)-1- piperidinyl)methyl)-6- chloro-7′-ethoxy-11′,12′- dimethyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 856.2 313

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4-(3- oxetanylmethyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 781.8 314

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-(((1R,4R)-5-(1- methylethyl)-2,5- diazabicyclo[2.2.1] hept-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 765.8 315

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-(((1S,4S)-5-(1- methylethyl)-2,5- diazabicyclo[2.2.1] hept-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 765.8 316

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4- ((5-methyl-1,2,4- oxadiazol-3-yl)methyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 807.9 317

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4- ((3-methyl-1,2,4- oxadiazol-5-yl)methyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 807.9 318

 

10

3-(4- (((1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-7′-yl)methyl-1- piperazinyl)propanenitrile 764.8 319

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((4-(3-methyl-3- oxetanyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 782.0 320

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((6-(1-methylethyl)-2,6- diazaspiro[3.3]hept-2- yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 765.9 321

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4- (1,2,4-oxadiazol-3- ylmethyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 793.2 322

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4-((4,5- dimethyl-1,3-oxazol-2- yl)methyl)-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 820.3 323

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((4-(1-methylethyl)-3- oxo-1-piperazinyl)methyl)- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.3 324

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 7′-(((3R,5S)-4-(2- methoxyethyl)-3,5- dimethyl-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 797.3 325

 

10

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aR)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2 yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihyrdro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aS)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 783.9

 

OR (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8S,9aR)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8S,9aS)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[l3]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13-dioxide 326

 

10

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aR)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8R,9aS)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 783.9

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8S,9aR)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((8S,9aS)-8- fluorooctahydro-2H- pyrido[1,2-a]pyrazin-2- yl)methyl)-7′-methoxy- 11′12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 327

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((4-(1-methylethyl)-1,4- diazepan-1-yl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.3 328

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((3R,5S)-3,5-dimethyl-4- (1-methylethyl)-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 781.3 329

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((3R,5S)-3,5-dimethyl-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 739.2 330

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((4- ethyl-3,3-dimethyl-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.2 331

 

10

 

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-((4-(1-methylethyl)-1,4- diazepan-1-yl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4-(1- methylethyl)-1,4-diazepan- 1-yl)methyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.2 332

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 7′-((4-(2-(2- methoxyethoxy)ethyl)-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 813.2 333

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-7′-((4-(2- methoxy-1,1- dimethylethyl)-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 797.2 334

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 7′-((4-(2-methoxyethyl)- 3,3-dimethyl-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 797.2 335

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-((4-tert-butyl-1- piperazinyl)methyl)-6- chloro-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.2 336

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-(((3R,5S)-3,4,5- trimethyl-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 753.2 337

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl- 7′-(((3S)-3-methyl-4-(1- methylethyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.2 338

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′-((4-(2- pyrimidinylmethyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 803.2 339

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4-(1,1- dioxido-3-thietanyl)-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 815.2 340

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((4-(1,4- dioxepan-6-yl)-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 811.2 341

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((3R,5S)-4-ethyl-3,5- dimethyl-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 767.2 342

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((4-(1,4- dioxepan-6-yl)-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 811.2 343

 

10

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- (((3R,5R)-3,5-dimethyl-4- (1-methylethyl)-1- piperazinyl)methyl)-7′- methoxy-11′,12′-dimethyl- 3,4-dihydro-2H, 5′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 781.2 344

 

10

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-7′-((3-(bis(2- methoxyethyl)aniino)-1- azetidinyl)methyl)-6- chloro-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 813.2 346

 

5, 9 Example 367, (Step 11)

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-12′-(2- hydroxyethyl)-7′-methoxy- 11′-methyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 797.2 347

 

5, 9

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′,12′- dimethyl-7′-propoxy-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 795.3 349

 

5, Example 348 (Step 2), 9

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′,12′- dimethyl-7′-(2- methylpropoxy)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 809.2 350

 

5, Example 348 (Step 2), 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-11′,12′- dimethyl-7′-(2- methylpropoxy)-7′-((9aR)- octahydro-2H-pyrido[1,2- a]pyrazin-2-ylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 807.4 351

 

5, Example 348 (Step 2), 9

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′,12′- dimethyl-7′-propoxy-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 795.3 352

5, Example 348 (Step 2), 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-11′,12′- dimethyl-7′-((4-(3- oxetanyl)-1- piperazinyl)methyl)-7′- propoxy-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 795.3 353

5, Example 348 (Step 2), 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-11′,12′- dimethyl-7′-((9aR)- octahydro-2H-pyrido[1,2- a]pyrazin-2-ylmethyl)-7′- propoxy-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 793.4 354

 

5, Example 348 (Step 2), 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-11′,12′- dimethyl-7′-(2- methylpropoxy)-7′-((9aR)- octahydro-2H-pyrido[1,2- a]pyrazin-2-ylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 807.3 355

 

5, Example 348 (Step 2), 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-11′,12′- dimethyl-7′-(2- methylpropoxy)-7′-((4-(3- oxetanyl)-1- piperazinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 809.3 356

 

5, Example 348 (Step 2, 9)

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-11′,12′- dimethyl-7′-(2- methylpropoxy)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 809.4 357

 

9, Example 367 (Step 11)

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-12′-(2- hydroxyethyl)-7′-methoxy- 11′-methyl-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 797.4 360

See example 18 (Step 14)

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′-methyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-12′- yl)acetaldehyde 793.3 361

 

See example 367 (Steps 12, 13)

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-7′-methoxy-11′- methyl-12′-(2-(4- morpholinyl)ethyl)-3,4- dihydro2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 866.4 365

 

See example 367 (Step 13)

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-7′- methoxy-11′-methyl-12′- (2-(4-morpholinyl)ethyl)- 7′-((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 864.3 368

 

5, Example 348 (Step 2), 8

(1S,3′R,6′R,7′R,8′E,11′S, 12′R)-6-chloro-11′,12′- dimethyl-7 ’ -(((3 R)-3 - methyl-4-(2-propanyl)-1- piperazinyl)methyl)-7’- propoxy-3,4-dihvdro- 2H,15’H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~ 19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 795.3 369

 

4, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 7′-((9aS)- hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)- ylmethyl)-12′-(2- methoxyethyl)-11′-methyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 826.2 370

 

4, 8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-ethoxy- 12′-(2-methoxyethyl)-11′- methyl-7′-((9aR)- octahydro-2H-pyrido[1,2- a]pyrazin-2-ylmethyl)-3,4- dihydro-2H,15[H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 824.3 371

 

8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 7′-((4-(2-methoxy-1- (methoxymethyl)ethyl)-1- piperazinyl)methyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 814.2 372

 

8

(1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-methoxy- 11′,12′-dimethyl-7′- ((9aR)-octahydro-2H- pyrido[1,2-a]pyrazin-2- ylmethyl)-3,4-dihydro- 2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3,6~ .0~19,24~]pentacosa[8,16,18, 24]tetraen]-15′-one 13′,13′-dioxide 766.3

Example 100001 (1S,3′R,6′R,7′S, 8′E,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[2]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Step 1: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[2]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide and (1S,3′R,6′R,7′S,8′F, 11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-Spiro[naphthalene-1,22′-[2]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a 250 mL round-bottomed flask was added 1,3-dithiane (4.79 g, 39.8 mmol) and THF (100 mL). The mixture was cooled to −78° C. and n-butyllithium (1.6 M solution in hexane, 22.5 mL, 36.1 mmol) was added over 8 min. The solution was stirred in the −78° C. bath for 30 min. In a separate 100 mL flask was added (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide and THF (5 mL). To this was added lanthanum(III) chloride bis lithium chloride complex solution (0.6 M in THF, 60.1 mL, 36.1 mmol) and this was stirred for 5 min at room temperature. The solution was then cooled to −78° C. and added via cannula to the dithiane solution. After 2.5 h at −78° C., the solution was treated with sat NH₄Cl and water. The pH of the solution was adjusted to pH=4 with aqueous 10% citric acid and aqueous NaHCO₃. The solution was extracted with EtOAc and the combined extracts were filtered through Celite. The extracts were washed with water and brine and then dried (Na₂SO₄) and concentrated to afford a mixture of (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide and (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide as a brown oil which was carried on directly to the next step. MS (ESI, +ve ion) m/z 717.5 (M+H)⁺.

Step 2: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide and (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro [naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a resealable vial was added the mixture of (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide and (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (6.81 g, 9.49 mmol) and THF (100 mL). The mixture was cooled to 0° C. and potassium bis(trimethylsilyl)amide (1 M in THF, 38.0 mL, 38.0 mmol) was added over 10 min. The solution was stirred at 0° C. for 5 min and then iodomethane (2.36 mL, 38.0 mmol) was added over 3 min. After 2.5 h at 0° C., the solution was poured into saturated NH₄Cl and the pH was adjusted to 4 with 1 M citric acid. The solution was extracted with EtOAc and the combined extracts were washed with brine, dried (Na₂SO₄) and concentrated onto silica. Purification by silica gel chromatography (0% to 35% EtOAc/heptane, with 0.3% AcOH, 330 g Redi-Sep Gold column) afforded (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (1.66 g, 2.27 mmol, 24% yield). MS (ESI, +ve ion) m/z 731.5 (M+H)⁺ and (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (4.69 g, 6.41 mmol, 68% yield). MS (ESI, +ve ion) m/z 731.5 (M+H)⁺.

Step 3: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide

To a 250 mL round-bottomed flask equipped with a reflux condenser was added (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(1,3-dithian-2-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (1.63 g, 2.23 mmol), acetonitrile (40 mL) and water (10 mL). The mixture was heated to 50° C. and calcium carbonate (1.12 g, 11.1 mmol) and iodomethane (1.38 mL, 22.3 mmol) were added. After 23 h at 50° C., the solution was poured into saturated NH₄Cl and water and then extracted with EtOAc. The combined extracts were washed with brine and then dried (Na₂SO₄) and concentrated onto silica. Purification by silica gel chromatography (0 to 40% EtOAc/heptane (both with 0.3% AcOH), Silicycle HP 120 g column) afforded (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (1.34 g, 2.09 mmol, 94% yield) as a white solid. MS (ESI, +ve ion) m/z 641.3 (M+H)⁺.

Step 4: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a room temperature solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′-carbaldehyde 13′,13′-dioxide (30 mg, 0.047 mmol) in MeOH (2 mL) and THF (0.5 mL), was added sodium borohydride (17 mg, 0.47 mmol). After 5 min at rt the solution was poured into saturated NaCl and then extracted with EtOAc. The combined extracts were dried (Na₂SO₄) and concentrated. Purification by silica gel chromatography (0% to 60% EtOAc (0.3% AcOH) in heptane (4 g column)) afforded (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(hydroxymethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (10 mg, 0.016 mmol, 50% yield) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.95-8.01 (m, 1H), 7.68 (d, J=8.61 Hz, 1H), 7.16-7.20 (m, 1H), 7.10 (dd, J=1.86, 13.99 Hz, 2H), 6.85-6.95 (m, 2H), 5.71-5.80 (m, 1H), 5.67 (d, J=0.98 Hz, 1H), 4.29-4.41 (m, 1H), 4.07 (d, J=4.89 Hz, 3H), 3.87-3.97 (m, 2H), 3.72 (br d, J=14.48 Hz, 1H), 3.26 (d, J=14.28 Hz, 1H), 3.10 (s, 3H), 2.96-3.04 (m, 1H), 2.72-2.80 (m, 2H), 2.56-2.65 (m, 1H), 2.44 (s, 1H), 1.75-2.28 (m, 9H), 1.55-1.71 (m, 1H), 1.50 (d, J=7.04 Hz, 3H), 1.50-1.41 (m, 1H), 1.06 (d, J=6.85 Hz, 3H). One exchangeable proton was not observed. MS (ESI, +ve ion) m/z 643.2 (M+H)⁺.

Example 100002 2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N-dimethylacetamide

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetic acid (60 mg, 0.089 mmol) was taken up in THF (1.8 mL) and lithium hydroxide (2.0 M in water, 0.18 mL, 0.36 mmol) was added. The mixture was stirred at room temperature for 10 min before being concentrated in vacuo to provide the lithium carboxylate of the starting material as an off-white solid that was used in the amide coupling. HATU (51.0 mg, 0.134 mmol) and dimethylamine (2.0 M in THF, 0.134 mL, 0.268 mmol) were added to a stirred suspension of the lithium carboxylate previously prepared in N,N-dimethylformamide (1.8 mL). The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was diluted with water and EtOAc and transferred to a separatory funnel. 1.0 M HCl was added and the phases were mixed. The organic layer was separated and washed sequentially with 1.0 M LiCl and brine then dried over magnesium sulfate and concentrated under reduced pressure. Purification via silica gel flash chromatography using a gradient of 50% to 100% EtOAc+0.3% AcOH in heptane afforded 2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N-dimethylacetamide (38 mg, 0.054 mmol, 61% yield) as a white solid. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.71 (d, J=8.48 Hz, 1H) 7.17 (dd, J=8.77, 2.19 Hz, 1H) 7.07-7.11 (m, 1H) 7.01-7.04 (m, 1H) 6.95-7.00 (m, 1H) 6.88-6.93 (m, 1H) 5.71-5.92 (m, 2H) 4.00-4.11 (m, 3H) 3.84 (br d, J=15.20 Hz, 1H) 3.70 (br d, J=14.03 Hz, 1H) 3.30 (d, J=14.32 Hz, 1H) 3.17 (s, 3H) 3.08-3.15 (m, 2H) 3.06 (s, 3H) 3.01 (s, 1H) 2.94 (s, 3H) 2.65-2.87 (m, 3H) 2.39-2.65 (m, 3H) 2.02-2.21 (m, 4H) 1.51-1.97 (m, 11H) 1.30-1.47 (m, 5H) 1.05 (d, J=6.14 Hz, 3H). MS (ESI, +ve) m/z 666.2 [M-OMe]⁺.

Example 100003 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′ [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Step 1: (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

A solution of 2-bromopyridine (105 μL, 1.1 mmol) in THF (4 mL) was cooled to −78° C. under nitrogen atmosphere. A solution of n-butyllithium in hexanes (2.5 M, 422 μL, 1.1 mmol) was added dropwise and the reaction mixture was stirred for 30 min. A solution of (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′ [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (300 mg, 0.5 mmol) in THF (1 mL) was added dropwise and the reaction mixture was allowed to warn to room temperature overnight. An aqueous saturated solution of NH₄Cl was added and the reaction mixture was extracted with EtOAc. The organic phase was separated, washed with brine and concentrated under reduced pressure. The yellow solid was purified by column chromatography on silica gel, eluting with a gradient of 0 to 35% EtOAc (containing 0.3% HOAc)/hexane to obtain a mixture of (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide as a light-yellow solid (129 mg). The mixture was used in the next step without additional purification. MS (ESI, +ve ion) m/z 676.0 (M+H)⁺.

Step 2: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′ [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

The mixture of (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (129 mg, 0.19 mmol) was dissolved in THF (5 mL) and the solution was cooled with a water bath. Sodium hydride (60% dispersion in mineral oil, 201 mg, 5 mmol) was added in one portion. After 15 min, iodomethane (624 μL, 10 mmol) was added. An additional portion of each NaH and MeI were added after 2 h. An aqueous saturated solution of NH₄Cl was added and the reaction mixture was extracted with EtOAc The solvent was removed under reduced pressure. The concentrate was purified by preparative reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 μm, C18, 110 Å, 100×50 mm, 0.1% TFA in CH₃CN/H₂O, gradient 10% to 100% over 20 min to afford 21 mg of [(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-1′,12′-dimethyl-7′-(2-pyridinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide, the second eluting peak, as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.15 (m, 3H) 1.24-1.34 (m, 2H) 1.48 (m, 3H) 1.61-1.80 (m, 2H) 1.83-1.93 (m, 2H) 1.95-2.07 (m, 3H) 2.19-2.32 (m, 3H) 2.62-2.82 (m, 5H) 3.06 (s, 3H) 3.11-3.21 (m, 2H) 3.70 (m, 1H) 3.96-4.01 (m, 1H) 4.04-4.09 (m, 1H) 4.17 (m, 1H) 5.86-6.02 (m, 2H) 6.92-6.97 (m, 1H) 6.99-7.03 (m, 1H) 7.09 (d, J=8.02 Hz, 2H) 7.18 (dd, J=8.41, 1.96 Hz, 1H) 7.65-7.71 (m, 2H) 8.34-8.40 (m, 2H) 9.02 (d, J=5.09 Hz, 1H). MS (ESI, +ve ion) m/z 690.0 (M+H)⁺.

Example 100004 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(3-pyridazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Step 1: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-pyridazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a solution of 2,2,6,6-tetramethylpiperidine (1.06 mL, 6.3 mmol) in THF (28 mL) that was cooled to 0° C. was added a solution of n-butyllithium (2.5 M in THF, 2.4 mL, 6.0 mmol) under nitrogen atmosphere. The reaction was stirred at 0° C. for 25 minutes then cooled to −78° C. A solution of pyridazine (110 μL, 1.5 mmol) in THF (5 mL) was added dropwise, followed by a solution of (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′ [20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (300 mg, 0.502 mmol) in THF (3 mL). The reaction mixture was allowed to stir at −78° C. for 2 h and quenched by the addition of aqueous saturated ammonium chloride solution. The reaction mixture was extracted with EtOAc. The organic phase was separated, washed with brine and concentrated under reduced pressure to give the crude material. The crude material was purified by silica gel flash chromatography using a gradient of 50% to 100% EtOAc+0.3% AcOH in heptane to provide 106 mg of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-pyridazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide, the second eluting peak. MS (ESI, +ve ion) m/z 677.0 (M+H)⁺.

Step 2: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(3-pyridazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Sodium hydride (60% dispersion in mineral oil, 81 mg, 2.0 mmol) was added in one portion to a solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-pyridazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (137 mg, 0.2 mmol) in tetrahydrofuran (6.7 mL). After 5 min, iodomethane (251 μL, 4.1 mmol) was added and the reaction was stirred for 2 hours. MeOH (3 mL) was added and the reaction mixture was purified by preparative reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 μm, C18, 110 Å, 100×50 mm, 0.1% TFA in CH₃CN/H₂O, gradient 10% to 100% over 20 min. The desired fractions were combined and the solvent was removed under reduced pressure to obtain 92 mg of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(3-pyridazinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide as a tan solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.03 (d, J=6.06 Hz, 3H) 1.35 (d, J=6.65 Hz, 3H) 1.72-1.87 (m, 2H) 1.89-2.23 (m, 9H) 2.73-2.84 (m, 3H) 2.94-3.06 (m, 2H) 3.11 (s, 3H) 3.26 (d, J=14.48 Hz, 1H) 3.68 (d, J=7.04 Hz, 1H) 3.75 (d, J=14.48 Hz, 1H) 4.04-4.14 (m, 2H) 4.32 (d, J=15.06 Hz, 1H) 5.43 (br. s., 9H) 5.91 (d, J=16.24 Hz, 1H) 6.85-6.92 (m, 2H) 7.03 (s, 1H) 7.09 (s, 1H) 7.16-7.21 (m, 1H) 7.18 (d, J=8.61 Hz, 1H) 7.70 (d, J=8.41 Hz, 1H) 8.18 (br. s., 2H) 9.48 (br. s., 1H). MS (ESI, +ve ion) m/z 691.0 (M+H)⁺.

Example 100005 2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N-(2-methoxyethyl)-N-methylacetamide

Step 1: 2-methyl-2-propanyl ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate and 2-methyl-2-propanyl ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate

2-tert-Butoxy-2-oxoethylzinc chloride (0.5 M in diethyl ether, 48.6 mL, 24.28 mmol) was added to a stirred solution of (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (2.90 g, 4.86 mmol) in tetrahydrofuran (50 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous NH₄Cl (150 mL) and extracted with EtOAc (100 mL). The organic layer was separated, washed with 9:1 saturated aqueous NH₄Cl:30% aqueous NH₄OH (200 mL), washed with brine (100 mL), dried over MgSO₄, filtered, and concentrated in vacuo to provide a crude mixture of 2-methyl-2-propanyl ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate and 2-methyl-2-propanyl ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate that was azeotroped twice with toluene and used directly in the next step. MS (ESI, +ve) m/z 713.3 [M+H]⁺.

Step 2: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(2-hydroxyethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide and (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(2-hydroxyethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Lithium borohydride (2.0 M solution in tetrahydrofuran, 10.41 mL, 20.82 mmol) was added to a stirred solution of the crude mixture of 2-methyl-2-propanyl ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate and 2-methyl-2-propanyl ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate in tetrahydrofuran (25 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h. Additional lithium borohydride (2.0 M solution in tetrahydrofuran, 5.21 mL, 10.4 mmol) was added, followed by dropwise addition of methanol (1.69 mL, 41.6 mmol). The reaction mixture was stirred at room temperature for 24 h. Additional methanol (1.687 mL, 41.6 mmol) was added, and the reaction mixture was stirred for another 2.5 h. The reaction mixture was slowly quenched with saturated aqueous NH₄Cl (75 mL) and extracted twice with EtOAc (75 mL). The combined organic layers were separated, washed with brine (60 mL), dried over MgSO₄, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 10% MeOH in DCM) provided a mixture of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(2-hydroxyethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide and (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(2-hydroxyethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (2.58 g, 4.01 mmol, 96% yield) as a white solid. MS (ESI, +ve) m/z 643.2 [M+H]⁺.

Step 3: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((dimethyl(2-methyl-2-propanyl)silyl)oxy)ethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Imidazole (1.274 g, 18.72 mmol) and tert-butyldimethylsilyl chloride (1.41 g, 9.36 mmol) were added to a stirred mixture of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(2-hydroxyethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide and (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(2-hydroxyethyl)-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (3.01 g, 4.68 mmol) in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 72 h. Additional tert-butyldimethylsilyl chloride (1.41 g, 9.36 mmol) and imidazole (1.274 g, 18.72 mmol) were added, and the reaction mixture was stirred at room temperature for another 4 h. Additional reagents were added multiple times while stirring at room temperature until the reaction progressed no further upon addition. The reaction mixture was quenched with saturated aqueous NH₄Cl (125 mL) and extracted with DCM (75 mL). The organic layer was separated, dried over MgSO₄, filtered, and concentrated in vacuo. The resulting residue was resubjected to the original reaction conditions and stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous NH₄Cl (125 mL) and extracted with DCM (75 mL). The organic layer was separated, dried over MgSO₄, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 50% EtOAc in heptane) provided (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((dimethyl(2-methyl-2-propanyl)silyl)oxy)ethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (453 mg, 0.598 mmol, 13% yield), the second diastereomer to elute from the column, as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.99 (1H, s) 7.69 (1H, d, J=8.41 Hz) 7.18 (1H, dd, J=8.51, 2.25 Hz) 7.09 (1H, d, J=2.15 Hz) 6.92-6.96 (3H, m) 5.71-5.78 (1H, m) 5.59 (1H, d, J=16.04 Hz) 4.55 (1H, br. s.) 3.96-4.19 (5H, m) 3.67-3.82 (2H, m) 3.25 (1H, d, J=14.28 Hz) 3.02 (1H, dd, J=15.16, 10.27 Hz) 2.68-2.86 (2H, m) 2.35-2.47 (1H, m) 2.26-2.36 (1H, m) 2.12-2.24 (3H, m) 1.77-2.08 (6H, m) 1.65-1.77 (1H, m) 1.51-1.62 (1H, m) 1.46 (3H, d, J=7.04 Hz) 1.36-1.45 (1H, m) 1.25-1.32 (1H, m) 1.07 (3H, d, J=6.06 Hz) 0.91 (9H, s) 0.10 (6H, d, J=3.33 Hz). MS (ESI, +ve) m/z 757.2 [M+H]⁺.

Step 4: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((dimethyl(2-methyl-2-propanyl)silyl)oxy)ethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Sodium hydride (60% dispersion in mineral oil, 119 mg, 2.97 mmol) was added to a stirred solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((dimethyl(2-methyl-2-propanyl)silyl)oxy)ethyl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (225 mg, 0.297 mmol) and iodomethane (0.185 mL, 2.97 mmol) in tetrahydrofuran (2 mL). The reaction mixture was stirred at room temperature for 17 h. The reaction mixture was quenched with saturated aqueous NH₄Cl (50 mL) and extracted with EtOAc (70 mL). The organic layer was separated, washed with brine (50 mL), dried over MgSO₄, filtered, and concentrated in vacuo to provide crude (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((dimethyl(2-methyl-2-propanyl)silyl)oxy)ethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide that was used directly in the next step. MS (ESI, +ve) m/z 793.3 [M+Na]⁺.

Step 5: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-hydroxyethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.356 mL, 0.356 mmol) was added to a stirred solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-((dimethyl(2-methyl-2-propanyl)silyl)oxy)ethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (229 mg, 0.297 mmol) in tetrahydrofuran (1.5 mL). The reaction mixture was stirred at room temperature for 3.5 h. Additional tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.356 mL, 0.356 mmol) was added, and the reaction mixture was stirred for another 3 h. The reaction mixture was concentrated. Chromatographic purification of the residue (silica gel, 0 to 100% (EtOAc with 0.3% AcOH) in heptane) provided (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-hydroxyethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (178 mg, 0.271 mmol, 91% yield) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.10 (1H, s) 7.68 (1H, d, J=8.61 Hz) 7.18 (1H, dd, J=8.51, 2.25 Hz) 7.09 (1H, d, J=2.15 Hz) 6.88-6.96 (3H, m) 5.75-5.83 (1H, m) 5.64 (1H, d, J=16.24 Hz) 4.29-4.37 (1H, m) 4.02-4.15 (2H, m) 3.91-3.99 (1H, m) 3.80-3.88 (2H, m) 3.72 (1H, d, J=14.28 Hz) 3.25 (1H, d, J=14.28 Hz) 3.11 (3H, s) 3.02 (1H, dd, J=14.96, 10.66 Hz) 2.69-2.85 (2H, m) 2.59 (1H, q, J=9.06 Hz) 2.34-2.47 (2H, m) 2.12-2.24 (2H, m) 1.76-2.06 (8H, m) 1.58-1.67 (1H, m) 1.50 (3H, d, J=7.04 Hz) 1.38 (1H, t, J=12.91 Hz) 1.06 (3H, d, J=6.85 Hz). MS (ESI, +ve) m/z 657.2 [M+H]⁺.

Step 6: ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetaldehyde

Dess-Martin periodinane (67.4 mg, 0.159 mmol) was added to a stirred mixture of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(2-hydroxyethyl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (87 mg, 0.13 mmol) and sodium bicarbonate (111 mg, 1.32 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was quenched with saturated aqueous NaHCO₃ (25 mL) and extracted with EtOAc (30 mL). The organic layer was separated, washed with 1 M aqueous Na₂S₂O₃ (20 mL), washed with brine (20 mL), dried over MgSO₄, filtered, and concentrated in vacuo to provide crude ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetaldehyde that was used directly in the next step.

Step 7: ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetic acid

A solution of potassium phosphate monobasic (361 mg, 2.66 mmol) and sodium chlorite (240 mg, 2.66 mmol) in water (2 mL) was added to a stirred mixture of ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetaldehyde (174 mg, 0.266 mmol) and 2-methyl-2-butene (1.407 mL, 13.28 mmol) in tert-butanol (2 mL). The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was diluted with EtOAc (50 mL), washed with 1 M aqueous HCl (40 mL), washed with 1 M Na₂S₂O₃ (40 mL), washed with brine (40 mL), dried over MgSO₄, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% (EtOAc with 0.3% AcOH) in heptane) provided ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetic acid (142 mg, 0.212 mmol, 80% yield) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.11 (1H, s) 7.68 (1H, d, J=8.41 Hz) 7.17 (1H, d, J=8.41 Hz) 7.08 (1H, s) 6.87-6.95 (3H, m) 5.80-5.90 (1H, m) 5.72 (1H, d, J=15.85 Hz) 4.36 (1H, q, J=7.17 Hz) 4.07 (2H, s) 3.99 (1H, d, J=15.65 Hz) 3.71 (1H, d, J=14.48 Hz) 3.16-3.27 (5H, m) 3.01 (1H, dd, J=15.55, 10.86 Hz) 2.71-2.84 (3H, m) 2.66 (1H, q, J=9.00 Hz) 2.42 (1H, quin, J=9.15 Hz) 2.12-2.26 (2H, m) 2.01-2.09 (1H, m) 1.83-2.01 (5H, m) 1.79 (1H, d, J=7.24 Hz) 1.57-1.69 (1H, m) 1.51 (3H, d, J=7.04 Hz) 1.35 (1H, t, J=13.11 Hz) 1.06 (3H, d, J=6.65 Hz). MS (ESI, +ve) m/z 671.2 [M+H]⁺.

Step 8: 2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N-(2-methoxyethyl)-N-methylacetamide

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetic acid (28 mg, 0.042 mmol) was taken up in THF (0.5 mL) and lithium hydroxide (2.0 M in water, 0.083 mL, 0.17 mmol) was added. The mixture was stirred at room temperature for 10 min before being concentrated in vacuo to provide the lithium carboxylate of the starting material as an off-white solid that was used in the amide coupling. HATU (31.7 mg, 0.083 mmol) and N-(2-methoxyethyl)methylamine (0.022 mL, 0.21 mmol) were added to a stirred suspension of the lithium carboxylate previously prepared in N,N-dimethylformamide (0.50 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous NH₄Cl (20 mL) and extracted with EtOAc (30 mL). The organic layer was separated, washed with brine (15 mL), dried over MgSO₄, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% (EtOAc with 0.3% AcOH) in heptane) followed by chromatographic purification (silica gel, 0 to 100% EtOAc in heptane) provided 2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N-(2-methoxyethyl)-N-methylacetamide (23 mg, 0.031 mmol, 74% yield) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.27 (0.4H, s) 8.10 (0.6H, s) 7.69 (1H, d, J=8.61 Hz) 7.17 (1H, dd, J=8.41, 2.15 Hz) 7.08 (1H, d, J=1.96 Hz) 6.90-7.06 (3H, m) 5.84-5.90 (1H, m) 5.72-5.83 (1H, m) 4.28 (0.6H, q, J=7.04 Hz) 4.19 (0.4H, q, J=7.04 Hz) 4.05 (1.2H, s) 4.04 (0.8H, s) 3.95 (0.4H, d, J=10.17 Hz) 3.91 (0.6H, d, J=10.17 Hz) 3.52-3.77 (4H, m) 3.22-3.34 (7H, m) 2.97-3.19 (6H, m) 2.57-2.82 (4H, m) 2.38-2.54 (1H, m) 1.99-2.23 (4H, m) 1.72-1.99 (5H, m) 1.57-1.68 (1H, m) 1.46-1.51 (3H, m) 1.27-1.37 (1H, m) 1.04-1.11 (3H, m). MS (ESI, +ve) m/z 742.2 [M+H]⁺.

Example 100006 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-(2-(1-azetidinyl)-2-oxoethyl)-6-chloro-7′-methoxy-1′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetic acid (28 mg, 0.042 mmol) was taken up in THF (0.5 mL) and lithium hydroxide (2.0 M in water, 0.083 mL, 0.17 mmol) was added. The mixture was stirred at room temperature for 10 min before being concentrated in vacuo to provide the lithium carboxylate of the starting material as an off-white solid that was used in the amide coupling. HATU (31.7 mg, 0.083 mmol) and azetidine (0.014 mL, 0.209 mmol) were added to a stirred suspension of the lithium carboxylate previously prepared in N,N-dimethylformamide (0.25 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous NH₄Cl (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, washed with brine (10 mL), dried over MgSO₄, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% (EtOAc with 0.3% AcOH) in heptane) followed by chromatographic purification (silica gel, 0 to 100% EtOAc in heptane) provided (1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-(2-(1-azetidinyl)-2-oxoethyl)-6-chloro-7′-methoxy-1′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (22 mg, 0.031 mmol, 74% yield) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.21 (1H, br s) 7.68 (1H, d, J=8.61 Hz) 7.13-7.20 (1H, m) 7.06-7.09 (1H, m) 6.88-6.97 (3H, m) 5.70-5.86 (2H, m) 4.23-4.39 (3H, m) 3.98-4.11 (5H, m) 3.70 (1H, d, J=14.28 Hz) 3.22-3.32 (2H, m) 3.08-3.18 (4H, m) 2.81-2.88 (1H, m) 2.67-2.79 (2H, m) 2.33-2.46 (2H, m) 2.19-2.31 (2H, m) 1.72-2.19 (9H, m) 1.56-1.69 (1H, m) 1.49 (3H, d, J=6.85 Hz) 1.25-1.36 (1H, m) 1.06 (3H, d, J=6.65 Hz). MS (ESI, +ve) m/z 710.2 [M+H]⁺.

Example 100007 and Example 100016 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′,11′,12′-trimethyl-7′-(2-(4-morpholinyl)ethoxy)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (Example 100007) and (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (Example 100016)

Step 1: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Lanthanum(III) chloride bis(lithium chloride) complex (0.5 M solution in THF, 0.616 mL, 0.308 mmol) was added to a stirred solution of (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (184 mg, 0.308 mmol) in tetrahydrofuran (3 mL) at 0° C. The mixture was stirred at 0° C. for 45 min before methylmagnesium bromide (3.0 M solution in diethyl ether, 0.462 mL, 1.39 mmol) was added dropwise via syringe. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was quenched with saturated aqueous NH₄Cl (30 mL) and extracted with EtOAc (45 mL). The organic layer was separated, washed with brine (30 mL), dried over MgSO₄, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 75% (EtOAc with 0.3% AcOH) in heptane) provided (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (92 mg, 0.150 mmol, 49% yield), the second diasteromer to elute from the column, as a white solid. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ 7.71 (d, J=8.6 Hz, 1H), 7.18 (dd, J=2.2, 8.5 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 7.00-6.89 (m, 3H), 5.90-5.76 (m, 2H), 4.35-4.24 (m, 1H), 4.11-4.04 (m, 2H), 3.84 (br d, J=14.9 Hz, 1H), 3.73 (d, J=14.3 Hz, 1H), 3.28 (d, J=14.3 Hz, 1H), 3.05 (dd, J=10.4, 15.3 Hz, 1H), 2.86-2.70 (m, 2H), 2.46-2.33 (m, 1H), 2.27 (q, J=9.3 Hz, 1H), 2.18-2.10 (m, 1H), 2.07 (br d, J=2.5 Hz, 1H), 2.05-2.01 (m, 2H), 2.02-1.91 (m, 3H), 1.89-1.78 (m, 3H), 1.69-1.60 (m, 1H), 1.52 (s, 3H), 1.47 (d, J=7.2 Hz, 3H), 1.44-1.36 (m, 1H), 1.04 (d, J=6.8 Hz, 3H). MS (ESI, +ve) m/z 613.3 [M+H]⁺.

Step 2: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′,11′,12′-trimethyl-7′-(2-(4-morpholinyl)ethoxy)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (33 mg, 0.054 mmol), 4-(2-bromoethyl)morpholine hydrobromide (296 mg, 1.08 mmol), and sodium hydride (60% dispersion in mineral oil, 86 mg, 2.2 mmol) were mixed in N,N-dimethylformamide (1.5 mL). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was quenched with saturated aqueous NH₄Cl (20 mL) and extracted two times with EtOAc (30 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO₄, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 50% to 100% EtOAc in DCM until the starting material eluted and then 0 to 10% (2 M NH₃ in MeOH) in DCM) provided (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′,11′,12′-trimethyl-7′-(2-(4-morpholinyl)ethoxy)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (25 mg, 0.034 mmol, 64% yield) as an off-white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.68 (1H, d, J=8.41 Hz) 7.17 (1H, dd, J=8.41, 2.15 Hz) 7.08 (1H, d, J=2.15 Hz) 6.89-6.96 (3H, m) 5.82 (1H, ddd, J=15.85, 9.59, 2.74 Hz) 5.65 (1H, d, J=15.85 Hz) 4.29 (1H, q, J=7.11 Hz) 4.00-4.11 (2H, m) 3.83 (1H, d, J=14.67 Hz) 3.68-3.77 (5H, m) 3.33-3.46 (2H, m) 3.26 (1H, d, J=14.28 Hz) 3.00 (1H, dd, J=15.16, 10.66 Hz) 2.69-2.84 (2H, m) 2.52-2.61 (6H, m) 2.40 (1H, quin, J=8.95 Hz) 2.28 (1H, q, J=9.13 Hz) 1.74-2.21 (9H, m) 1.52-1.64 (1H, m) 1.48 (3H, d, J=7.04 Hz) 1.33-1.43 (4H, m) 1.04 (3H, d, J=6.85 Hz). MS (ESI, +ve) m/z 726.3 [M+H]⁺.

Example 100008 2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N-methyl-N-(2-methyl-2-propanyl)acetamide

A drop of DMF was added to a stirred solution of oxalyl chloride (10 μL, 0.11 mmol) and ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetic acid (37 mg, 0.055 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 20 min before being concentrated in vacuo. The resulting yellow residue was taken up in dichloromethane (1 mL) and N-tert-butylmethylamine (0.066 mL, 0.55 mmol) was added. The reaction mixture was stirred at room temperature for 40 min. The reaction mixture was quenched with saturated aqueous NH₄Cl (20 mL) and extracted with EtOAc (30 mL). The organic layer was separated, washed with brine (20 mL), dried over MgSO₄, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 50% (EtOAc with 0.3% AcOH) in heptane) provided 2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N-methyl-N-(2-methyl-2-propanyl)acetamide (18 mg, 0.024 mmol, 44% yield) as an off-white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.01 (1H, s) 7.68 (1H, d, J=8.41 Hz) 7.17 (1H, dd, J=8.51, 2.25 Hz) 7.08 (1H, d, J=1.96 Hz) 6.88-6.96 (3H, m) 5.68-5.81 (2H, m) 4.33 (1H, q, J=7.43 Hz) 4.07 (2H, s) 3.85 (1H, d, J=15.06 Hz) 3.71 (1H, d, J=14.28 Hz) 3.22-3.36 (2H, m) 3.11 (3H, s) 3.01-3.09 (5H, m) 2.68-2.84 (2H, m) 2.59 (1H, d, J=15.85 Hz) 2.33-2.44 (1H, m) 2.06-2.23 (2H, m) 1.74-2.06 (7H, m) 1.55-1.66 (1H, m) 1.24-1.52 (13H, m) 1.06 (3H, d, J=6.65 Hz). MS (ESI, +ve) m/z 762.3 [M+Na]⁺.

Example 100009 2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N-methylacetamide

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-Chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetic acid (50 mg, 0.074 mmol) was taken up in THF (2 mL) and lithium hydroxide (2.0 M in water, 0.149 mL, 0.358 mmol) was added. The mixture was stirred at room temperature for 10 min before being concentrated in vacuo to provide the lithium carboxylate of the starting material as an off-white solid that was used in the amide coupling. HATU (42.0 mg, 0.112 mmol) and methylamine (2.0 M in THF, 0.112 mL, 0.223 mmol) were added to a stirred suspension of the lithium carboxylate previously prepared in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and EtOAc and transferred to a separatory funnel. 1.0 M HCl was added and the phases were mixed. The organic layer was separated and washed sequentially with 1.0 M LiCl and brine then dried over magnesium sulfate and concentrated under reduced pressure. Purification via silica gel flash chromatography using a gradient of 50% to 100% EtOAc with 0.3% AcOH in heptane afforded 2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N-methylacetamide (44 mg, 0.064 mmol, 86% yield) as a white solid. ¹H NMR (300 MHz, DICHLOROMETHANE-d₂) δ 7.69-7.79 (m, 1H) 7.19 (br dd, J=8.84, 1.10 Hz, 1H) 7.12 (s, 1H) 6.88-7.03 (m, 3H) 6.74-6.86 (m, 1H) 5.75-5.89 (m, 1H) 5.62-5.73 (m, 1H) 4.21-4.36 (m, 1H) 4.09 (s, 2H) 3.91-4.04 (m, 1H) 3.72 (br d, J=15.05 Hz, 1H) 3.29 (br d, J=14.03 Hz, 1H) 3.16 (s, 3H) 2.92-3.09 (m, 2H) 2.73-2.90 (m, 6H) 2.51-2.66 (m, 2H) 2.37-2.49 (m, 1H) 1.67-2.25 (m, 11H) 1.48 (br d, J=7.02 Hz, 3H) 1.22-1.43 (m, 6H) 1.06 (br d, J=6.58 Hz, 3H). MS (ESI, +ve) m/z 652.0 [M-OMe]⁺.

Example 100010 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Step 1: methyl ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate

A flame dried round bottom flask was charged with tetrahydrofuran (6.28 mL) and lithium diisopropylamide (2.0 M solution in heptane/tetrahydrofuran/ethylbenzene, 7.54 mL, 15.1 mmol). The solution was cooled to −78° C. then a solution of methyl acetate (1.197 mL, 15.07 mmol) in tetrahydrofuran (6.28 mL) was added dropwise and the reaction was stirred at −78° C. for 45 minutes. The flask was equipped with an addition funnel which was then charged with a solution of (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (1.5 g, 2.5 mmol) in tetrahydrofuran (12.56 mL). The reaction was stirred at −78° C. for 30 minutes. The reaction was quenched with water and warmed to room temperature. The reaction was diluted with water and EtOAc and transferred to a separatory funnel. 1 M HCl was added. The phases were mixed and the organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude residue was purified via silica gel flash chromatography using a gradient of 20% to 70% EtOAc with 0.3% AcOH in heptane to afford methyl ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate (0.666 g, 0.992 mmol, 40% yield), the second eluting diastereomer, as a white solid. ¹H NMR (300 MHz, DICHLOROMETHANE-d₂) δ 8.06-8.25 (m, 1H) 7.74 (d, J=8.62 Hz, 1H) 7.20 (br d, J=8.77 Hz, 1H) 7.13 (s, 1H) 6.96 (s, 2H) 6.92 (s, 1H) 5.64-5.81 (m, 2H) 4.06-4.25 (m, 3H) 3.80 (s, 3H) 3.75 (br d, J=14.03 Hz, 1H) 3.70 (s, 1H) 3.31 (d, J=14.18 Hz, 1H) 3.00-3.11 (m, 1H) 2.91-3.00 (m, 1H) 2.69-2.87 (m, 3H) 2.32-2.56 (m, 2H) 1.79-2.21 (m, 9H) 1.59-1.71 (m, 2H) 1.46 (d, J=7.16 Hz, 4H) 1.34-1.39 (m, 4H) 1.06 (d, J=6.58 Hz, 3H). MS (ESI, +ve) m/z 671.2 [M+H]⁺.

Step 2: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a solution of methyl ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)acetate (0.343 g, 0.511 mmol) in THF (10.22 mL) was added lithium hydroxide (2.0 M in water, 0.639 mL, 1.28 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure and used without further purification. To a suspension of the lithium carboxylate previously generated in DMF (2.5 mL) was added HATU (0.069 g, 0.18 mmol) followed by pyrrolidine (0.050 mL, 0.60 mmol). The reaction was stirred at room temperature for 30 minutes. The reaction was diluted with water and EtOAc and transferred to a separatory funnel. 1.0 M HCl was added and the phases were mixed. The organic layer was separated then washed sequentially with 1.0 M LiCl and brine then dried over magnesium sulfate and concentrated under reduced pressure. Purification via silica gel flash chromatography using a gradient of 75% to 100% EtOAc with 0.3% AcOH in heptane afforded (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (0.0608 g, 0.086 mmol, 71% yield) as a white solid. MS (ESI, +ve) m/z 710.3 [M+H]⁺.

Step 3: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

A solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (0.0608 g, 0.086 mmol) in THF (0.856 mL) was cooled to 0° C. before adding sodium hydride (0.017 g, 0.428 mmol). The reaction was stirred for 30 minutes then iodomethane (0.053 mL, 0.856 mmol) was added and the reaction was warmed to room temperature and stirred for 1 hour. A larger portion of iodomethane (0.150 mL) was added and the reaction was allowed to stir at room temperature overnight. An additional portion of MeI (0.15 mL) was added and the reaction was continued at room temperature for 6 h. The reaction was quenched with water and diluted with water and EtOAc. The reaction was transferred to a separatory funnel and 1 M HCl was added. The phases were mixed and the organic layer was separated, washed with brine and dried over magnesium sulfate. The crude material was purified via silica gel flash chromatography using 100% EtOAc with 0.6% AcOH. The reaction was repeated a second time on the same scale and the material from both reactions was combined and further purified by preparative supercritical fluid chromatography SFC using the following conditions: Diol Column (21.2×250 mm, 5 m); 20% MeOH with 20 mM NH₃ in CO₂ to afford (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(2-oxo-2-(1-pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (0.018 g, 0.025 mmol, 15% yield) as a white solid. ¹H NMR (300 MHz, DICHLOROMETHANE-d₂) δ 7.75 (br d, J=8.18 Hz, 1H) 7.20 (br d, J=8.48 Hz, 1H) 7.12 (br s, 2H) 7.00-7.06 (m, 1H) 6.90-6.98 (m, 1H) 5.75-5.99 (m, 2H) 4.13-4.24 (m, 1H) 4.10 (s, 2H) 3.86-3.96 (m, 1H) 3.74 (br d, J=14.32 Hz, 1H) 3.57-3.68 (m, 2H) 3.41-3.54 (m, 2H) 3.34 (br d, J=14.62 Hz, 1H) 3.07-3.25 (m, 4H) 3.03 (br d, J=15.93 Hz, 1H) 2.69-2.92 (m, 2H) 2.46-2.67 (m, 2H) 2.04-2.26 (m, 4H) 1.74-2.03 (m, 9H) 1.49-1.73 (m, 9H) 1.46 (br d, J=6.72 Hz, 3H) 1.29-1.41 (m, 2H) 1.03-1.14 (m, 3H). MS (ESI, +ve) m/z 692.2 [M-OMe]⁺.

Example 100011 (1S,3′R,6′R,7′S,8′E, 11′S, 12′R)-6-chloro-7′-(4-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Step 1: (1S,3′R,6′,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-hydroxy-1′,12′-dimethyl-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia 1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a cooled (−78° C.) solution of 4-(tert-butyldimethylsilyl)-1-butyne (2.50 mL, 12.1 mmol) in tetrahydrofuran (30 mL) was added 2.5 M butyllithium in toluene (4.0 mL, 10 mmol) dropwise via syringe over a period of 15 min. After 1 h, a solution of (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (1.008 g, 1.688 mmol) in THF (10 mL) was added dropwise and stirred for 1 h. The reaction was quenched with pH 7 buffer (10 mL) and warmed to room temperature. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine and dried over Na₂SO₄. The solution was filtered, evaporated onto silica gel and purified by flash chromatography (Isco, 40 g) eluting with 0.3% AcOH in EtOAc:0.3% AcOH in heptane (0:1 to 1:3) to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (468 mg, 36% yield) as a white solid. MS (ESI, +ve ion) m/z 763.4 (M+1)⁺.

Step 2: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a cooled (0° C.) solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (0.510 g, 0.653 mmol) in tetrahydrofuran (10 mL) was added 60% sodium hydride in mineral oil (0.211 g, 5.28 mmol) in portions. After 15 min iodomethane (0.160 mL, 2.58 mmol) was added and the reaction was allowed to warm to room temperature overnight. The reaction mixture was quenched with pH 7 buffer and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3×) then the combined organic layers were washed with brine, evaporated onto silica gel and purified by flash chromatography (Isco, 25 g) eluting with 0.3% AcOH in EtOAc: 0.3% AcOH in heptane (0:1 to 1:3) to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-methoxy-1′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (368 mg, 71% yield) as a white solid. MS (ESI, +ve ion) m/z 795.4 (M+1)⁺.

Step 3: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-hydroxy-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a room temperature solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (0.365 g, 0.459 mmol) in tetrahydrofuran (5 mL) was added 1 M tetrabutylammonium fluoride in tetrahydrofuran (1.5 mL, 1.5 mmol) via syringe. The reaction was evaporated onto silica gel and purified by flash chromatography (Isco (12 gram HP)) eluting with 0.3% AcOH in EtOAc: 0.3% AcOH in heptane (0:1 to 1:1) to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-hydroxy-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (279 mg, 89% yield) as a white solid. MS (ESI, +ve ion) m/z 681.3 (M+1)⁺.

Step 4: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a cooled (0° C.) solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-hydroxy-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (0.023 g, 0.034 mmol) in dichloromethane (1 mL) was added triethylamine (0.020 mL, 0.14 mmol) followed by methanesulfonyl chloride (0.015 mL, 0.19 mmol) and the reaction was stirred for 20 min. To the reaction was added a slurry of (S)-octahydropyrazino[2,1-c]morpholine dihydrochloride (0.067 g, 0.31 mmol) and triethylamine in dichloromethane (1 mL) and the reaction was stirred at room temperature for 85 h and at 45° C. for 4 h. The reaction was cooled to room temperature, diluted with DCM, evaporated onto silica gel and purified by flash chromatography (Isco, 4 g) eluting with 25% EtOH/EtOAc: heptane (0:1 to 1:0) to give (12.6 mg, 46% yield) light-yellow solid. ¹H NMR (400 MHz, CD₂Cl₂) δ 7.72 (d, J=8.41 Hz, 1H), 7.20 (s, 1H), 7.17 (dd, J=8.51, 2.05 Hz, 1H), 7.09 (d, J=2.15 Hz, 1H), 6.85-6.98 (m, 2H), 6.20-6.39 (m, 1H), 5.52 (d, J=15.84 Hz, 1H), 4.32 (d, J=15.65 Hz, 1H), 4.26 (d, J=6.46 Hz, 1H), 4.14 (d, J=12.13 Hz, 1H), 4.00-4.11 (m, 2H), 3.75 (dd, J=11.15, 2.93 Hz, 1H), 3.69 (d, J=14.08 Hz, 1H), 3.51-3.64 (m, 2H), 3.27 (d, J=14.28 Hz, 1H), 3.07-3.19 (m, 4H), 3.01 (dd, J=15.26, 10.37 Hz, 1H), 2.87 (d, J=7.43 Hz, 1H), 2.74-2.83 (m, 3H), 2.50-2.72 (m, 8H), 2.37-2.49 (m, 1H), 2.08-2.27 (m, 7H), 1.77-1.99 (m, 5H), 1.57-1.75 (m, 2H), 1.34-1.51 (m, 4H), 1.03 (d, J=6.85 Hz, 3H). MS (ESI, +ve ion) m/z 805.3 (M+1)⁺.

Example 100012 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Step 1: (1S,3′R,6′R,7′S,8′E,11′S, 12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-hydroxy-11,12′-dimethyl-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24-]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11S,12R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-hydroxy-11,12′-dimethyl-3,4-dihydro-2H, 15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a cooled (−78° C.) solution of 4-(tert-butyldimethylsilyloxy)-1-butyne (0.600 mL, 2.91 mmol) in tetrahydrofuran (9 mL) was added 2.5 M butyllithium solution in toluene (1.00 mL, 2.50 mmol) dropwise over a period of 10 min. After 1 h, a solution of (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (0.249 g, 0.417 mmol) in THF (2 mL) was added dropwise via syringe. After 1 h the reaction mixture was quenched with pH 7 buffer, partitioned between EtOAc and brine and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco, 12 g) eluting with 0.3% AcOH in EtOAc: 0.3% AcOH in heptane (0:1 to 1:3) to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (254 mg, 78% yield) as a white solid. MS (ESI, +ve ion) m/z 784.5 (M+1)⁺.

Step 2: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a cooled (0° C.) solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (0.254 g, 0.325 mmol) in tetrahydrofuran (5 mL) was added 60% NaH in mineral oil (0.105 g, 2.63 mmol) portion wise. After 10 min iodomethane (0.080 mL, 1.3 mmol) was added via syringe and the reaction was allowed to warm to room temperature overnight. The reaction mixture was quenched with pH 7 buffer and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3×) then the combined organic layers were washed with brine, evaporated onto silica gel and purified by flash chromatography (Isco, 25 g) eluting with 0.3% AcOH in EtOAc: 0.3% AcOH in heptane (0:1 to 1:3) to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-methoxy-1′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (173 mg, 67% yield) as a white solid. MS (ESI, +ve ion) m/z 796.3 (M+1)⁺.

Step 3: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-hydroxy-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-hydroxy-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a room temperature solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-((dimethyl(2-methyl-2-propanyl)silyl)oxy)-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (0.173 g, 0.217 mmol) in tetrahydrofuran (3 mL) was added 1 M tetrabutylammonium fluoride solution in THF (0.700 mL, 0.700 mmol). The reaction was partitioned between EtOAc and brine and the organic layer was evaporated onto silica gel and purified by flash chromatography (Isco (12 gram)) eluting with 25% EtOH/EtOAc:heptane (0:1 to 1:0) to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-hydroxy-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-hydroxy-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (91 mg, 61% yield) as a white solid.

Step 4: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a cooled (0° C.) solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-(4-hydroxy-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide AND (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-(4-hydroxy-1-butyn-1-yl)-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (0.057 g, 0.084 mmol) in dichloromethane (1.5 mL) was added triethylamine (0.060 mL, 0.43 mmol) followed by methanesulfonyl chloride (0.035 mL, 0.45 mmol) resulting in a yellow mixture. After 15 min morpholine (0.075 mL, 0.86 mmol) was added the reaction was stirred for 1 h. To the reaction was added morpholine (0.035 mL) and the reaction was stirred at room temperature overnight. The reaction mixture was partitioned between CH₂C12 and brine and the aqueous layer was extracted with CH₂C12 and brine (2×). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give 110 mg of a yellow tar. The material was purified following a 2-step SFC method: (Step 1: Cyano column, 20% isopropanol/20 mM NH₃ 80 g/min Step 2: MSA column, 40% MeOH/20 mM NH₃) to give the first eluting isomer, (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (6 mg, 10% yield) as a white crystalline solid. ¹H NMR (400 MHz, CD₂Cl₂) δ 7.72 (d, J=8.41 Hz, 1H), 7.19 (s, 1H), 7.17 (dd, J=8.51, 2.25 Hz, 1H), 7.09 (d, J=2.15 Hz, 1H), 6.80-6.95 (m, 2H), 6.23-6.39 (m, 1H), 5.52 (d, J=15.26 Hz, 1H), 4.39 (d, J=14.87 Hz, 1H), 4.26-4.34 (m, 1H), 4.01-4.14 (m, 2H), 3.69 (d, J=14.08 Hz, 1H), 3.58 (t, J=4.69 Hz, 4H), 3.26 (d, J=14.28 Hz, 1H), 3.12 (s, 3H), 3.00 (dd, J=15.16, 10.47 Hz, 1H), 2.63-2.86 (m, 5H), 2.51-2.63 (m, 2H), 2.51-2.63 (m, 2H), 2.34-2.48 (m, 5H), 2.11-2.24 (m, 2H), 2.04-2.11 (m, 1H), 1.75-2.03 (m, 6H), 1.59-1.72 (m, 1H), 1.46 (d, J=7.24 Hz, 3H), 1.39 (t, J=13.20 Hz, 1H), 1.03 (d, J=6.65 Hz, 3H). MS (ESI, +ve ion) m/z 750.3 (M+1)⁺.

Example 100013 2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-7′-yl)-N,N-dimethylacetamide

N-Butyllithium solution (1.6 M in hexane, 0.83 mL, 1.3 mmol) was added to a solution of diisopropylamine (0.19 mL, 1.3 mmol) in THF (1.0 mL) at 0° C. The solution was stirred at 0° C. for 2 minutes then dimethyl acetamide (0.12 mL, 1.3 mmol) was added. The reaction was then stirred at 0° C. for 7 min. Then a solution of (1S,3′R,6′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene]-7′,15′-dione 13′,13′-dioxide (0.040 g, 0.067 mmol) in THF (1.3 mL) was added and maintained at 0° C. for 17 min. The reaction was quenched with saturated ammonium chloride solution and acidified with 1 N HCl to pH 2-3 and extracted with EtOAc. The organic phase was washed with brine and dried over anhydrous sodium sulfate and the filtrate was concentrated under reduced pressure to give the crude product that was purified by preparatory SFC chromatography (CC4 250 mm×21 mm column, Phenomenex; 33 g/minute MeOH (2 M ammonia as a modifier)+27 g/minute CO₂ on Thar 200 SFC; outlet pressure=100 bar; temperature=40° C.; wavelength=246 nm; 2.0 mL injection of 30 mg/mL sample solution of 1:1 DCM:MeOH (2.0 mL) to give 2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2h-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-7′-yl)-n,n-dimethylacetamide (17 mg, 37% yield) as the first eluting diasteromer. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ 7.71 (d, J=8.4 Hz, 1H), 7.16 (dd, J=2.2, 8.5 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 7.04-6.98 (m, 2H), 6.97-6.91 (m, 1H), 5.23 (br s, 1H), 4.17-4.06 (m, 3H), 3.68 (d, J=14.3 Hz, 1H), 3.58 (d, J=15.3 Hz, 1H), 3.23 (d, J=14.3 Hz, 1H), 3.17 (s, 3H), 3.02 (dd, J=9.7, 15.4 Hz, 1H), 2.97 (s, 3H), 2.84-2.67 (m, 4H), 2.65-2.54 (m, 1H), 2.46 (quin, J=9.0 Hz, 1H), 2.10-1.97 (m, 2H), 1.96-1.72 (m, 5H), 1.68-1.42 (m, 5H), 1.39 (d, J=7.2 Hz, 3H), 1.37-1.35 (m, 1H), 1.35-1.18 (m, 2H), 0.99 (d, J=6.7 Hz, 3H). MS (ESI, +ve ion) m/z 686.2 (M+1)⁺.

Example 100014 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Step 1: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-7′,11′,12′-TRIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE

(1S,3′R,6′R,8′E,11′S,12′R)-6-Chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (200 mg, 0.335 mmol) was dissolved in THF (3.00 mL) and cooled to 0° C. Lanthanum (III) chloride bis(lithium chloride) complex solution (0.6 M in THF, 0.63 mL, 0.34 mmol) was added to the solution and the solution was stirred for 45 minutes. The methylmagnesium bromide (3.0 M in diethyl ether solution, 0.50 mL, 1.5 mmol) was added to the solution and allowed to warm to room temperature overnight. Another aliquot of methylmagnesium bromide (3.0 M in diethyl ether solution, 0.502 mL, 1.51 mmol) was added and the reaction was stirred for 30 minutes to completion then quenched with saturated ammonium chloride solution. This solution was then acidified to pH 6.5 and then extracted with EtOAc (2×50 mL). The combined organic layers were then washed with brine (1×20 mL) and dried over sodium sulfate. The residue was then purified by chromatography (silica, 20% to 100% EtOAc (0.3% HOAc):hexanes) to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (124 mg, 60% yield) as the second eluting diastereomer. MS (ESI, +ve ion) m/z 613.1 (M+1)⁺.

Step 2: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-METHOXY-7′,11′,12′-TRIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-Chloro-7′-hydroxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (30 mg, 0.049 mmol) was dissolved in tetrahydrofuran (1.0 mL) and cooled to 0° C. Sodium hydride (60% dispersion, 20 mg, 0.49 mmol) was then added and the resulting slurry was stirred for 20 minutes. The methyl iodide (0.031 mL, 0.49 mmol) was then added and the reaction mixture was stirred for 2.5 hours while slowly warming to room temperature. Another aliquot of sodium hydride (60% dispersion, 20 mg, 0.49 mmol) and methyl iodide (0.031 mL, 0.49 mmol) was added and the reaction was stirred for an additional 3.5 h to completion. The reaction was then quenched with dropwise addition of satd. ammonium chloride addition and the mixture was extracted with EtOAc (2×50 mL). The combined organic layers were then washed with brine (1×20 mL) and dried over sodium sulfate. The crude product was purified by chromatography (silica, 0 to 50% EtOAc/hexanes) to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide. (29 mg, 95% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 11.89 (s, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.27 (dd, J=2.1, 8.5 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.03 (dd, J=1.5, 8.1 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 6.79 (s, 1H), 5.72 (dd, J=3.2, 9.3 Hz, 1H), 5.65-5.55 (m, 1H), 4.16-4.08 (m, 1H), 4.07-3.94 (m, 2H), 3.69 (d, J=14.7 Hz, 1H), 3.59 (d, J=14.3 Hz, 1H), 3.24 (d, J=14.3 Hz, 1H), 3.08 (dd, J=9.6, 14.7 Hz, 1H), 2.94 (s, 3H), 2.84-2.62 (m, 2H), 2.36-1.60 (m, 12H), 1.43-1.36 (m, 1H), 1.33 (d, J=7.2 Hz, 3H), 1.30 (s, 3H), 0.96 (d, J=6.7 Hz, 3H). MS (ESI, +ve ion) m/z 627.2 (M+1)⁺.

Example 100015 (2S,3′R,6′R, 11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″-dihydro-2″H, 15′H-dispiro[1,4-dioxane-2,7′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide OR (2R,3′R,6′R, 11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″-dihydro-2″H, 15′H-dispiro[1,4-dioxane-2,7′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide

Step 1: (1S,3′R,6′R,8′E,11′S,12′R)-6-CHLORO-11′,12′-DIMETHYL-7′-METHYLIDENE-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.˜3,6˜.0˜19,24˜]PENTACOSA[8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE

A solution of methyltriphenylphosphonium bromide (1.80 g, 5.0 mmol) in THF (15 mL) was cooled to 0° C. N-butyllithium solution (2.5 M in hexanes, 1.8 mL, 4.5 mmol) was added dropwise and the solution was stirred at 0° C. for 10 minutes. The solution was added dropwise to a solution of (1S,3′R,6′R,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene]-7′,15′-dione 13′,13′-dioxide (0.30 g, 0.50 mmol) in THF (6.0 mL), cooled in ice bath, until the yellow color persisted. The solution was stirred at 0° C. for 12 min. The reaction mixture was added to stirred ice water (20 mL) and acidified with 1 N HCl to pH 2-4. The organic phase was separated and the aqueous was extracted with EtOAc (50 mL). The organic phase was washed with brine and dried over magnesium sulfate. The filtrate was concentrated to give crude product. The compound was purified by chromatography (silica, 0 to 50% EtOAc (0.3% HOAc:hexanes) to give (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-7′-methylidene-3,4-dihydro-2h, 15′h-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (290 mg, 97% yield). MS (ESI, +ve ion) m/z 595.2 (M+H)⁺.

Step 2: (1S,3′R,6′R,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-7′-(HYDROXYMETHYL)-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0^(3,6).0^(19,24)]PENTACOSA [8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE

The AD-Mix-alpha mixture (640 mg, 0.43 mmol) was dissolved in a mixture of tert-butanol (10.0 mL) and water (10.0 mL) and cooled to 0° C. (1S,3′R,6′R,8′E,11′S,12′R)-6-Chloro-11′,12′-dimethyl-7′-methylidene-3,4-dihydro-2h,15′h-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (255 mg, 0.428 mmol) was added and the reaction mixture was warmed slowly to room temperature overnight. Another 5.0 mL of t-BuOH was added to homogenize the mixture. The reaction was stirred overnight. Another 320 mg of AD-Mix-alpha mixture was added and the reaction was stirred for an additional three days. The reaction was quenched by adding 575 mg of sodium sulfite at 0° C. and stirring for 45 minutes. The mixture was then extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine (1×20 mL) and dried over sodium sulfate. The crude product was then purified by chromatography (silica, 0 to 100% EtOAc (+0.3% HOAc):heptanes) to give (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2h, 15′h-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (31 mg, 12% yield). MS (ESI, +ve ion) m/z 629.2 (M+H)⁺.

Step 3: (1S,3′R,6′R,11′S,12′R)-7′-((2-BROMOETHOXY)METHYL)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIEN]-15′-ONE 13′,13′-DIOXIDE

(1S,3′R,6′R,8′E,11′S,12′R)-6-Chloro-7′-hydroxy-7′-(hydroxymethyl)-11′,12′-dimethyl-3,4-dihydro-2h, 15′h-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (30.0 mg, 0.048 mmol) was dissolved in THF (1.0 mL) and cooled to 0° C. Sodium hydride (60% dispersion, 19.0 mg, 0.48 mmol) was added and the resulting slurry was stirred for ten minutes, then 2-bromoethyl trifluoromethanesulfonate (Ark Pharm Inc.) (61 mg, 0.24 mmol) was added and the reaction was allowed to slowly warm to room temperature over 45 minutes. The reaction was then quenched with slow addition of water (5 mL) and the mixture was extracted (2×25 mL) with ethyl acetate. The combined organic layers were washed with brine (1×15 mL) and then dried over magnesium sulfate. The residue was then purified by chromatography (silica, 0 to 50% EtOAc (+0.3% HOAc):hexanes) to give (1S,3′R,6′R,11′S,12′R)-7′-((2-bromoethoxy)methyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2h, 15′h-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide (25 mg, 71% yield). MS (ESI, +ve ion) m/z 739.1 (M+H)⁺.

Step 4: (2S,3′R,6′R,11′S,12′R,22′S)-6″-CHLORO-11′,12′-DIMETHYL-3″,4″-DIHYDRO-2″H, 15′H-DISPIRO[1,4-DIOXANE-2,7′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIENE-22′,1″-NAPHTHALEN]-15′-ONE 13′,13′-DIOXIDE OR (2R,3′R,6′R,11′S,12′R,22′S)-6″-CHLORO-11′,12′-DIMETHYL-3″,4″-DIHYDRO-2″H, 15′H-DISPIRO [1,4-DIOXANE-2,7′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0˜3,6˜.0˜19,24˜]PENT ACOSA[16,18,24]TRIENE-22′,1″-NAPHTHALEN]-15′-ONE 13′,13′-DIOXIDE

(1S,3′R,6′R, 11′S,12′R)-7′-((2-Bromoethoxy)methyl)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2h, 15′h-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]trien]-15′-one 13′,13′-dioxide (25.0 mg, 0.034 mmol) was then dissolved in DMF (0.5 mL) and sodium hydride (60% dispersion, 19 mg, 0.48 mmol) was added. This mixture was then heated to 85° C. for 10 minutes. The reaction mixture was then cooled to room temperature and quenched with dropwise addition of water (5 mL). This mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with 1 N LiCl solution (1×15 mL) and brine (1×10 mL) and dried over magnesium sulfate. The crude product was the purified by chromatography (silica, 0 to 50% EtOAc (+0.3% HOAc):hexanes) to give (2S,3′R,6′R, 11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″-dihydro-2″h, 15′h-dispiro[1,4-dioxane-2,7′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide or (2R,3′R,6′R,11′S,12′R,22′S)-6″-chloro-11′,12′-dimethyl-3″,4″-dihydro-2″h,15′h-dispiro[1,4-dioxane-2,7′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[16,18,24]triene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide (14 mg, 45% yield). ¹H NMR (400 MHz, MeOH) δ 7.73 (d, J=8.4 Hz, 1H), 7.17 (dd, J=2.2, 8.4 Hz, 1H), 7.13-7.08 (m, 2H), 7.02 (d, J=1.6 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 4.08 (s, 2H), 4.06-4.01 (m, 1H), 3.76 (d, J=11.9 Hz, 2H), 3.73-3.59 (m, 4H), 3.58-3.49 (m, 1H), 3.46-3.38 (m, 1H), 3.23-3.15 (m, 1H), 3.10 (dd, J=9.1, 15.4 Hz, 1H), 2.86-2.68 (m, 2H), 2.62-2.50 (m, 1H), 2.11-2.03 (m, 1H), 1.96-1.84 (m, 3H), 1.76-1.51 (m, 7H), 1.49-1.40 (m, 1H), 1.36 (d, J=7.0 Hz, 3H), 1.34-1.27 (m, 2H), 1.23-1.19 (m, 2H), 1.01 (d, J=6.8 Hz, 3H). MS (ESI, +ve ion) m/z 657.2 (M+H)⁺.

Example 100017 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a cooled (−78° C.) solution of 4-(but-3-yn-1-yl)morpholine (0.163 g, 1.171 mmol) in tetrahydrofuran (3 mL) was added 2.5 M butyllithium solution in toluene (0.400 mL, 1.00 mmol) dropwise via syringe. After 45 min, a solution of (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (0.100 g, 0.167 mmol) in THF (1 mL) was added dropwise. After 1 h, the reaction was quenched with saturated NH₄Cl (3 mL) and the mixture was warmed to room temperature. The mixture was extracted with dichloromethane (3×) and the combined organic layers were washed with brine and dried over Na₂SO₄. The solution was filtered and the filtrate was concentrated under reduced pressure to give an orange oil. The crude material was purified by preparative SFC (Waters Thar 200; Cyano Column (21.1×250 mm, 5 μm) with 18% methanol (20 mM NH₃), 82% carbon dioxide; flow rate=95 mL/min, column temperature=40° C., pressure=100 bar, detection at 220 nm) to give the first eluting diastereomer, (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(4-(4-morpholinyl)-1-butyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (32 mg, 26%) as a white solid. ¹H NMR (400 MHz, CD₂Cl₂) δ 7.72 (d, J=8.41 Hz, 1H), 7.13-7.24 (m, 2H), 7.09 (d, J=1.96 Hz, 1H), 6.83-6.96 (m, 2H), 6.25-6.41 (m, 1H), 5.75 (d, J=15.26 Hz, 1H), 4.38 (d, J=15.06 Hz, 1H), 4.29 (q, J=7.37 Hz, 1H), 3.97-4.13 (m, 2H), 3.69 (d, J=14.08 Hz, 1H), 3.58 (t, J=4.69 Hz, 4H), 3.26 (d, J=14.28 Hz, 1H), 3.00 (dd, J=15.26, 10.37 Hz, 1H), 2.47-2.87 (m, 7H), 2.29-2.46 (m, 5H), 1.80-2.21 (m, 9H), 1.61-1.72 (m, 1H), 1.44 (d, J=7.24 Hz, 3H), 1.33-1.41 (m, 1H), 1.03 (d, J=6.85 Hz, 3H). MS (ESI, +ve ion) m/z 736.2 (M+1)⁺.

Example 100018 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-(4-morpholinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-(4-morpholinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a cooled (−78° C.) solution of 4-(prop-2-yn-1-yl)morpholine (0.170 mL, 1.35 mmol, Ark Pharm, Inc.) in tetrahydrofuran (3 mL) was added butyllithium solution (2.5 M in toluene, 0.500 mL, 1.25 mmol) dropwise via syringe. After 45 min a solution of (1S,3′R,6′R,8′E,11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (0.100 g, 0.167 mmol) in THF (1 mL) was added dropwise. After 1 h, the reaction was quenched with saturated NH₄Cl (3 mL) and the mixture was warmed to room temperature. The mixture was extracted with DCM (3×) and the combined organic layers were washed with brine and dried over Na₂SO₄. The solution was filtered and the filtrate was concentrated under reduced pressure to give a yellow oil. The crude material was purified using preparative SFC (Premier (2×25 cm); 50% methanol/CO₂, 100 bar; 50 mL/min, 254 nm) to give the first eluting isomer, (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-(4-morpholinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-(3-(4-morpholinyl)-1-propyn-1-yl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (40 mg, 33% yield) as a solid. ¹H NMR (400 MHz, CD₂Cl₂) δ 7.71 (d, J=8.41 Hz, 1H), 7.12-7.23 (m, 2H), 7.09 (d, J=2.15 Hz, 1H), 6.84-6.97 (m, 2H), 6.22-6.40 (m, 1H), 5.78 (d, J=14.87 Hz, 1H), 4.25 (d, J=14.67 Hz, 2H), 4.07 (s, 2H), 3.70 (d, J=14.28 Hz, 1H), 3.59-3.66 (m, 4H), 3.56 (s, 2H), 3.25 (d, J=14.08 Hz, 1H), 3.02 (dd, J=15.16, 10.47 Hz, 1H), 2.67-2.89 (m, 2H), 2.51-2.65 (m, 5H), 2.33-2.49 (m, 1H), 2.02-2.16 (m, 4H), 1.76-2.01 (m, 7H), 1.62-1.73 (m, 1H), 1.43 (d, J=7.04 Hz, 3H), 1.34-1.41 (m, 1H), 1.04 (d, J=6.46 Hz, 3H). MS (ESI, +ve ion) m/z 722.2 (M+1)⁺.

Example 100019 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2R)-4-methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2S)-4-methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2S)-4-methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2R)-4-methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

To a solution of diisopropylamine (1.183 mL, 8.44 mmol) in tetrahydrofuran (4.22 mL) at 0° C. was added butyllithium (2.5 M in hexanes, 3.38 mL, 8.44 mmol) for 3 minutes. The solution was then cooled to −78° C. 4-Methyl-morpholin-3-one (0.887 mL, 8.44 mmol) was added dropwise and the solution was allowed to stir for 1 hour. (1S,3′R,6′R,8′E,11′S,12′R)-6-Chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (0.252 g, 0.422 mmol) in a solution of 0.5 mL of THF was added dropwise. Upon completion, saturated ammonium chloride aqueous solution was added. 1 N HCl was added until the pH reached 2-3 and the solution was extracted with EtOAc. The organic extract was washed with saturated NaCl, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP Ultra silica gel column (50 g), eluting with a gradient of 10% to 100% EtOAc:EtOH (3:1) in hexane with 0.5% AcOH. The material was further purified by preparative SFC using a Me-sulfone achiral column (21×150 mm, 5 m), 60% methanol with 20 mM NH₃, flow rate 60 mL/min, column temperature 40° C., pressure 100 bar, detection at 220 nm. The third isomer to elute was isolated to give (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2R)-4-methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2S)-4-methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2S)-4-methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-7′-((2R)-4-methyl-3-oxo-2-morpholinyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one. ¹H NMR (400 MHz, DMSO-d₆) δ 0.92 (d, J=6.06 Hz, 3H) 1.02 (br. s., 2H) 1.36 (t, J=12.72 Hz, 1H) 1.61 (br. s., 3H) 1.87 (br. s., 3H) 1.92-2.13 (m, 3H) 2.25 (d, J=7.63 Hz, 1H) 2.62-2.79 (m, 2H) 2.84 (s, 3H) 2.86-3.06 (m, 3H) 3.29 (br. s., 1H) 3.55 (d, J=13.50 Hz, 1H) 3.71 (br. s., 1H) 3.79-4.01 (m, 4H) 4.10 (d, J=13.30 Hz, 1H) 4.26 (br. s., 1H) 5.33 (br. s., 1H) 5.71 (d, J=15.45 Hz, 1H) 6.17 (br. s., 1H) 6.67-6.84 (m, 1H) 6.98-7.41 (m, 4H) 7.65 (d, J=8.61 Hz, 1H). MS (ESI, +ve ion) m/z 712.2 (M+1)⁺.

Example 100020 1-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N-dimethylmethanesulfonamide OR 1-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N-dimethylmethanesulfonamide

To a solution of N,N-dimethylmethanesulfonamide (206 mg, 1.68 mmol) in 2-methyltetrahydrofuran (4 mL) at 0° C. was added n-butyllithium (1.6 M in hexanes, 0.67 mL, 1.7 mmol), and the reaction was stirred at 0° C. for 5 min. (1S,3′R,6′R,8′E,11′S,12′R)-6-Chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (100 mg, 0.167 mmol) in 2-methyltetrahydrofuran (1 mL) was added at low temperature and after 15 min quenched with aqueous saturated NH₄Cl (50 mL), brine (50 mL) and EtOAc (100 mL). The organic layer was separated, dried (Na₂SO₄), filtered and concentrated onto silica. Purification by silica gel chromatography (0 to 100% EtOAc (0.3% AcOH) in heptane afforded 1-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N-dimethylmethanesulfonamide and 1-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N-dimethylmethanesulfonamide (70 mg, 0.10 mmol, 58% yield) as a mixture of isomers. The mixture was then purified by preparatory SFC chromatography (column: Welko-O1 250 mm×21 mm column, mobile phase: 65:35 (A:B) isocratic, A: liquid CO₂, B: methanol (20 mM NH₃), flow rate: 70 g/min, column temperature: 40° C., detection: UV at 220 nm), and the first eluting isomer 1-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N-dimethylmethanesulfonamide OR 1-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-13′,13′-dioxido-15′-oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-7′-yl)-N,N-dimethylmethanesulfonamide (10 mg, 0.014 mmol, 8% yield) was isolated. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.69 (d, J=8.41 Hz, 1H), 7.17 (dd, J=2.25, 8.51 Hz, 1H), 7.09 (d, J=2.15 Hz, 1H), 6.94 (s, 2H), 6.87 (s, 1H), 5.68-5.80 (m, 2H), 4.00-4.22 (m, 4H), 3.67-3.83 (m, 2H), 3.57 (br d, J=14.48 Hz, 1H), 3.20-3.32 (m, 2H), 3.05-3.16 (m, 1H), 2.96 (s, 6H), 2.89-2.93 (m, 1H), 2.69-2.83 (m, 2H), 2.38-2.50 (m, 1H), 2.03-2.17 (m, 3H), 1.85-2.02 (m, 3H), 1.72-1.84 (m, 2H), 1.58-1.70 (m, 2H), 1.46 (d, J=7.24 Hz, 3H), 1.32-1.41 (m, 1H), 1.06 (d, J=6.06 Hz, 3H). One exchangeable proton was not observed. MS (ESI, +ve ion) m/z 720.2 (M+H)⁺.

Table 2 lists compounds prepared by the General Methods outlined in the present specification.

TABLE 2 Examples Prepared by the General Methods MS Dat Exam- (M + 1)⁺ ple Unless Num- Noted ber Structure Name Otherwise 100001

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-(hydroxymethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 643.2 100002

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-dimethylacetamide 698.2 100003

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-7′-(2- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 690.2 100004

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-7′-(3- pyridazinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 691.2 100005

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo [14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-(2-methoxyethyl)-N- methylacetamide 742.2 100006

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-(2-(1- azetidinyl)-2-oxoethyl)-6-chloro-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 710.2 100007

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′,11′,12′-trimethyl-7′-(2-(4- morpholinyl)ethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 726.3 100008

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14]diazatetracyclo [14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-methyl-N-(2-methyl-2- propanyl)acetamide 762.3 100009

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-methylacetamide 684.2 100010

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-7′-(2-oxo-2- (1-pyrrolidinyl)ethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 724.2 100011

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-(4-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-yl)-1-butyn-1-yl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 805.3 100012

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-7′-(4-(4- morpholinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 750.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-7′-(4-(4- morpholinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100013

2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylacetamide 686.2 100014

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-7′,11′,12′-trimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 627.2 100015

(2S,3′R,6′R,11′S,12′R,22′S)-6″-chloro- 11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,4-dioxane-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalen]-15′-one 13′,13′- dioxide 657.2 OR OR

(2R,3′R,6′R,11′S,12′R,22′S)-6″-chloro- 11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,4-dioxane-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalen]-15′-one 13′,13′- dioxide 100016

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-7′,11′,12′-trimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 613.1 100017

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(4-(4- morpholinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 736.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(4-(4- morpholinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100018

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(3-(4- morpholinyl)-1 -propyn-1-yl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 722.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(3-(4- morpholinyl)-1-propyn-1-yl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100019

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-((2R)-4- methyl-3-oxo-2-morpholinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 712.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-((2S)-4- methyl-3-oxo-2-morpholinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-((2S)-4- methyl-3-oxo-2-morpholinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-((2R)-4- methyl-3-oxo-2-morpholinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100020

1-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylmethanesulfonamide 720.2 OR OR

1-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylmethanesulfonamide 100021

(1S,3′R,6′R,7′R)-6-chloro-7′-hydroxy-7′- (hydroxymethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 602.9 OR OR

(1S,3′R,6′R,7′S)-6-chloro-7′-hydroxy-7′- (hydroxymethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100022

(1S,3′R,6′R,7′S)-6-chloro-7′-hydroxy-7′- (hydroxymethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 603.0 OR OR

(1S,3′R,6′R,7′R)-6-chloro-7′-hydroxy-7′- (hydroxymethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100023

(1S,3′R,6′R,7′S)-6-chloro-7′-hydroxy-7′- methyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 587.2 OR OR

(1S,3′R,6′R,7′R)-6-chloro-7′-hydroxy-7′- methyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100024

(1S,3′R,6′R,7′R)-6-chloro-7′-hydroxy-7′- methyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 587.3 OR OR

(1S,3′R,6′R,7′S)-6-chloro-7′-hydroxy-7′- methyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100025

(1S,3′R,6′R,7′S)-6-chloro-7′-hydroxy-7′- (1-propyn-1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 611.0 OR OR

(1S,3′R,6′R,7′R)-6-chloro-7′-hydroxy-7′- (1-propyn-1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100026

(1S,3′R,6′R,7′R)-6-chloro-7′-hydroxy-7′- (1-propyn-1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 611.0 OR OR

(1S,3′R,6′R,7′S)-6-chloro-7′-hydroxy-7′- (1-propyn-1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100027

(1S,3′R,6′R,7′S)-6-chloro-7′-hydroxy- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene]-7′-carbonitrile 13′,13′-dioxide 598.0 OR OR

(1S,3′R,6′R,7′R)-6-chloro-7′-hydroxy- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene]-7′-carbonitrile 13′,13′-dioxide 100028

(1S,3′R,6′R,7′S,8′E,12′S)-6-chloro-7′- hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 599.2 OR OR

(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-7′- hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′S,8′E,12′S)-6-chloro-7′- hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-7′- hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100029

(1S,3′R,6′R,7′S,8′E,12′S)-6-chloro-7′- hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 599.2 OR OR

(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-7′- hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′S,8′E,12′S)-6-chloro-7′- hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-7′- hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100030

(1S,3′R,6′R,7′R,8′E,12′S)-6-chloro-7′- hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 599.2 OR OR

(1S,3′R,6′R,7′S,8′E,12′S)-6-chloro-7′- hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100031

(1S,3′R,6′R,7′S,12′S)-6-chloro-7′- hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 601.2 OR OR

(1S,3′R,6′R,7′R,12′R)-6-chloro-7′- hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′S,12′S)-6-chloro-7′- hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,12′R)-6-chloro-7′- hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100032

(1S,3′R,6′R,7′R,8′E,12′S)-6-chloro-7′- hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′one 13′,13′-dioxide 599.2 OR OR

(1S,3′R,6′R,7′S,8′E,12′R)-6-chloro-7′- hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,8′E,12′S)-6-chloro-7′- hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′S,8′E,12′R)-6-chloro-7′- hydroxy-7′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetra- cyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100033

(1S,3′R,6′R,7′S,8′S,13′R)-6-chloro-7′- hydroxy-7′,13′-dimethyl-3,4-dihydro- 2H,16′H-spiro[naphthalene-1,23′- [21]oxa[14]thia[1,15] diazapenta- cyclo[15.7.2.0~3,6~.0~8,10~.0~20,25~] hexacosa[17,19,25] trien]-16′-one 14′,14′-dioxide 613.2 OR OR

(1S,3′R,6′R,7′S,8′S,13′R)-6-chloro-7′- hydroxy-7′,13′-dimethyl-3,4-dihydro- 2H,16′H-spiro[naphthalene-1,23′- [21]oxa[14]thia[1,15] diazapenta- cyclo[15.7.2.0~3,6~.0~8,10~.0~20,25~] hexacosa[17,19,25] trien]-16′-one 14′,14′-dioxide OR OR

(1S,3′R,6′R,7′R,8′R,10′R,13′R)-6-chloro- 7′-hydroxy-7′,13′-dimethyl-3,4-dihydro- 2H,16′H-spiro[naphthalene-1,23′- [21]oxa[14]thia[1,15] diazapenta- cyclo[15.7.2.0~3,6~.0~8,10~.0~20,25~] hexacosa[17,19,25]trien]-16′-one 14′,14′-dioxide OR OR

(1S,3′R,6′R,7′R,8′R,10′R,13′R)-6-chloro- 7′-hydroxy-7′,13′-dimethyl-3,4-dihydro- 2H,16′H-spiro[naphthalene-1,23′- [21]oxa[14]thia[1,15] diazapentacyclo[15.7.2.0~3,6~.0~8,10~.0~20,25~] hexacosa[17,19,25]trien]-16′-one 14′,14′-dioxide 100034

(1S,3′R,6′R,7′S,8′E,12′R)-6-chloro-12′- ethyl-7′-hydroxy-7′-(hydroxymethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 629.0 OR OR

(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′- ethyl-7′-hydroxy-7′-(hydroxymethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100035

(1S,3′R,6′R,7′S,12′R)-6-chloro-12′-ethyl- 7′-hydroxy-7′-(hydroxymethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 631.1 OR OR

(1S,3′R,6′R,7′R,12′R)-6-chloro-12′-ethyl- 7′-hydroxy-7′-(hydroxymethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100036

(1S,3′R,6′R,7′R,12′R)-6-chloro-12′-ethyl- 7′-hydroxy-7′-(hydroxymethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 631.1 OR OR

(1S,3′R,6′R,7′S,12′R)-6-chloro-12′-ethyl- 7′-hydroxy-7′-(hydroxymethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100037

(1S,3′R,6′R,7′S,12′R)-6-chloro-12′-ethyl- 7′-methoxy-7′-(methoxymethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 659.1 OR OR

(1S,3′R,6′R,7′R,12′R)-6-chloro-12′-ethyl- 7′-methoxy-7′-(methoxymethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100038

(1S,3′R,6′R,7′R,12′R)-6-chloro-12′-ethyl- 7′-methoxy-7′-(methoxymethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 659.1 OR OR

(1S,3′R,6′R,7′S,12′R)-6-chloro-12′-ethyl- 7′-methoxy-7′-(methoxymethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100039

(1S,3′R,6′R,7′S,12′R)-6-chloro-12′-ethyl- 7′-hydroxy-7′-(methoxymethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 645.1 OR OR

(1S,3′R,6′R,7′R,12′R)-6-chloro-12′-ethyl- 7′-hydroxy-7′-(methoxymethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100040

(1S,3′R,6′R,7′R,12′R)-6-chloro-12′-ethyl- 7′-hydroxy-7′-(methoxymethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 645.1 OR OR

(1S,3′R,6′R,7′S,12′R)-6-chloro-12′-ethyl- 7′-hydroxy-7′-(methoxymethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100041

(1S,3′R,6′R,7′S,12′R)-6-chloro-12′-ethyl- 7′-(hydroxymethyl)-7′-methoxy-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 645.1 OR OR

(1S,3′R,6′R,7′R,12′R)-6-chloro-12′-ethyl- 7′-(hydroxymethyl)-7′-methoxy-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100042

ethyl (((1S,3′R,6′R,7′S,12′R)-6-chloro-7′- (2-ethoxy-2-oxoethoxy)-12′-ethyl-13′,13 ′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)methoxy)acetate 803.1 OR OR

ethyl (((1S,3′R,6′R,7′R,12′R)-6-chloro-7′- (2-ethoxy-2-oxoethoxy)-12′-ethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)methoxy)acetate 100043

(2S,3′R,6′R,12′R,22′S)-6″-chloro-12′- ethyl-3″,4″-dihydro-2″H,6H,15′H- dispiro[1,4-dioxane-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalene]-6,15′-dione 13′,13′-dioxide 671.0 OR OR

(2R,3′R,6′R,12′R,22′S)-6″-chloro-12′- ethyl-3″,4″-dihydro-2″H,6H,15′H- dispiro[1,4-dioxane-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalene]-6,15′-dione 13′,13′-dioxide 100044

(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′- ethyl-7′-hydroxy-7′-(trifluoromethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 667.0 OR OR

(1S,3′R,6′R,7′S,8′E,12′R)-6-chloro-12′- ethyl-7′-hydroxy-7′-(trifluoromethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13-dioxide 100045

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′- (trifluoromethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 667.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′- (trifluoromethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100046

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′- (trifluoromethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 667.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′- (trifluoromethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100047

(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′- ethyl-7′-hydroxy-7′-(trifluoromethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 667.0 OR OR

(1S,3′R,6′R,7′S,8′E,12′R)-6-chloro-12′- ethyl-7′-hydroxy-7′-(trifluoromethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13 ′-dioxide 100048

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-7′,11′,12′-trimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 615.2 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-7′,11′,12′-trimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100049

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-7′,11′,12′-trimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 615.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-7′,11′,12′-trimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100050

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetonitrile 638.3 OR OR

((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetonitrile 100051

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetonitrile 638.2 OR OR

((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetonitrile 100052

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-7′-(hydroxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 631.2 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-7′-(hydroxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100053

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-7′-(hydroxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 631.3 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-7′-(hydroxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100054

(3′R,4S,6′R,11′S,12′R,22′S)-6″-chloro- 11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,3-dioxolane-4,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalene]- 2,15′-dione 13′,13′-dioxide 657.3 OR OR

(3′R,4R,6′R,11′S,12′R,22′S)-6″-chloro- 11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,3-dioxolane-4,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalene]-2,15′-dione 13′,13′-dioxide 100055

(3′R,4R,6′R,11′S,12′R,22′S)-6″-chloro- 11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,3-dioxolane-4,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalene]- 2,15′-dione 13′,13′-dioxide 657.3 OR OR

(3′R,4S,6′R,11′S,12′R,22′S)-6″-chloro- 11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,3-dioxolane-4,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalene]- 2,15′-dione 13′,13′-dioxide 100056

(1S,3′R,6′R,7′S,11′S,13′S,14′R)-6-chloro- 7′-hydroxy-13′,14′-dimethyl-3,4-dihydro- 2H,17′H-spiro[naphthalene-1,24′- [22]oxa[15]thia[1,16] diazapenta- cyclo[16.7.2.1~7,11~.0~3,6~.0~21,26~] octacosa[9,18,20,26]tetraen]-17′-one 15′,15′-dioxide 639.1 OR OR

(1S,3′R,6′R,7′R,11′S,13′S,14′R)-6-chloro- 7′-hydroxy-13′,14′-dimethyl-3,4-dihydro- 2H,17′H-spiro[naphthalene-1,24′- [22]oxa[15]thia[1,16] diazapenta- cyclo[16.7.2.1~7,11~.0~3,6~.0~21,26~] octacosa[9,18,20,26] tetraen]-17′-one 15′,15′-dioxide 100057

(1S,3′R,6′R,7′S,11′R,13′S,14′R)-6-chloro- 7′-hydroxy-13′,14′-dimethyl-3,4-dihydro- 2H,17′H-spiro[naphthalene-1,24′- [22]oxa[15]thia[1,16] diazapenta- cyclo[16.7.2.1~7,11~.0~3,6~.0~21,26~] octacosa[9,18,20,26]tetraen]-17′-one 15′,15′-dioxide 639.1 100058

(1S,3′R,6′R,7′R,11′S,13′S,14′R)-6-chloro- 7′-hydroxy-13′,14′-dimethyl-3,4-dihydro- 2H,17′H-spiro[naphthalene-1,24′- [22]oxa[15]thia[1,16] diazapenta- cyclo[16.7.2.1~7,11~.0~3,6~.0~21,26~] octacosa[9,18,20,26]tetraen]-17′-one 15′,15′-dioxide 639.0 100059

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2-methylpropanenitrile 666.3 OR OR

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2- methylpropanenitrile 100060

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2- methylpropanenitrile 666.3 OR OR

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2- methylpropanenitrile 100061

methyl (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl-15′- oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene]-7′-carboxylate 13′,13′-dioxide 657.3 OR OR

methyl (1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl-15′- oxo-3,4-dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene]-7′-carboxylate 13′,13′-dioxide 100062

(1S,3′R,6′R,7′S,11′R,13′S,14′R)-6-chloro- 7′-hydroxy-13′,14′-dimethyl-3,4-dihydro- 2H,17′H-spiro[naphthalene-1,24′- [22]oxa[15]thia[1,16] diazapenta- cyclo[16.7.2.1~7,11~.0~3,6~.0~21,26~] octacosa[18,20,26]trien]-17′-one 15′,15′-dioxide 641.1 100063

(1S,3′R,6′R,7′S,9′R,11′S,12′R)-6-chloro- 9′-(dimethylamino)-7′-hydroxy-7′,11′,12′- trimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 657.8 OR OR

(1S,3′R,6′R,7′S,9′S,11′S,12′R)-6-chloro- 9′-(dimethylamino)-7′-hydroxy-7′,11′,12′- trimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,9′R,11′S,12′R)-6-chloro- 9′-(dimethylamino)-7′-hydroxy-7′,11′,12′- trimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,9′S,11′S,12′R)-6-chloro- 9′-(dimethylamino)-7′-hydroxy-7′,11′,12′- trimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100064

(1S,3′R,6′R,7′S,9′R,11′S,12′R)-6-chloro- 7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 644.2 OR OR

(1S,3′R,6′R,7′S,9′S,11′S,12′R)-6-chloro- 7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,9′R,11′S,12′R)-6-chloro- 7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,9′S,11′S,12′R)-6-chloro- 7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100065

(1S,3′R,6′R,7′S,9′R,11′S,12′R)-6-chloro- 7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 644.2 OR OR

(1S,3′R,6′R,7′S,9′S,11′S,12′R)-6-chloro- 7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,9′R,11′S,12′R)-6-chloro- 7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,9′S,11′S,12′R)-6-chloro- 7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H, 15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100066

(1S,3′R,6′R,7′S,9′R,11′S,12′R)-6-chloro- 7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 643.8 OR OR

(1S,3′R,6′R,7′S,9′S,11′S,12′R)-6-chloro- 7′-hydroxy-7,11,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,9′R,11′S,12′R)-6-chloro- 7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,9′S,11′S,12′R)-6-chloro- 7′-hydroxy-7′,11′,12′-trimethyl-9′- (methylamino)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [2.0]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100067

diethyl (((1S,3′R,6′R,7′S,8′E,11′S,12′R)- 6-chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl) (difluoro)methyl)phosphonate 785.2 OR OR

diethyl (((1S,3′R,6′R,7′S,8′E,11′S,12′R)- 6-chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl) (difluoro)methyl)phosphonate 100068

diethyl (((1S,3′R,6′R,7′S,8′E,11′S,12′R)- 6-chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl) (difluoro)methyl)phosphonate 785.2 OR OR

diethyl (((1S,3′R,6′R,7′R,8′E,11′S,12′R)- 6-chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl) (difluoro)methyl)phosphonate 100069

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-(difluoromethyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 649.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-(difluoromethyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~.0~19,24~] pentacosa[16,18,24] tetraen]-15′-one 13′,13′-dioxide 100070

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-(difluoromethyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 649.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-(difluoromethyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100071

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-(difluoromethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 663.0 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-(difluoromethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100072

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′- ((methylsulfonyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 691.1 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′- ((methylsulfonyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100073

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′- ((methylsulfonyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 691.0 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′- ((methylsulfonyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100074

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(((S)- methylsulfinyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 675.0 AND AND

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(((R)- methylsulfinyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(((S)- methylsulfinyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide AND AND

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(((R)- methylsulfinyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100075

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(((S)- methylsulfinyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 675.3 AND AND

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(((R)- methylsulfinyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(((S)- methylsulfinyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide AND AND

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(((R)- methylsulfinyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100076

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- ethyl-7′-hydroxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 629.3 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- ethyl-7′-hydroxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100077

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylacetamide 684.2 OR OR

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-dimethylacetamide 100078

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-dimethylacetamide 684.2 OR OR

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-dimethylacetamide 100079

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- ethyl-7′-hydroxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 629.1 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- ethyl-7′-hydroxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100080

((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)acetonitrile 640.3 OR OR

((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)acetonitrile 100081

((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)acetonitrile 640.3 OR OR

((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)acetonitrile 100082

2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylacetamide 686.3 100083

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-diethylacetamide 712.2 OR OR

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-diethylacetamide 100084

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-diethylacetamide 712.2 OR OR

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-diethylacetamide 100085

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(2-(4- morpholinyl)-2-oxoethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 726.1 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(2-(4- morpholinyl)-2-oxoethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100086

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-(4- morpholinyl)-2-oxoethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 728.1 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-(4- morpholinyl)-2-oxoethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100087

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-(4- morpholinyl)-2-oxoethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 728.1 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-(4- morpholinyl)-2-oxoethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100088

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-(2- (dimethylamino)ethyl)-7′-hydroxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 672.3 100089

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1- piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 726.3 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1- piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100090

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1- piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 726.2 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1- piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100091

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-(1- piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 712.2 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-(1- piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100092

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-(1- piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 712.4 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-(1- piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100093

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-(2- (3,3-difluoro-1-azetidinyl)ethyl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 720.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-(2- (3,3-difluoro-1-azetidinyl)ethyl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100094

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′-(2- (3,3-difluoro-1-azetidinyl)ethyl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 720.2 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-(2- (3,3-difluoro-1-azetidinyl)ethyl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100095

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-(4- morpholinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 714.3 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-(4- morpholinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100096

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-(4- morpholinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 714.3 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-(4- morpholinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100097

((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)acetic acid 658.8 OR OR

((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)acetic acid 100098

2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[l,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-methylacetamide 671.9 OR OR

2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-methylacetamide 100099

1-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N- dimethylmethanesulfonamide 722.2 OR OR

1-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N- dimethylmethanesulfonamide 100100

1-((1S,3′R,6′R,7′S,1l′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N- dimethylmethanesulfonamide 722.3 OR OR

1-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N- dimethylmethanesulfonamide 100101

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetic acid 656.8 100102

(3′R,6′R,11′S,12′R,22′S)-6″-chloro- 11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,3-dioxolane-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalen]- 15′-one 13,13-dioxide 643.3 100103

2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-methylacetamide 671.9 OR OR

2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-methylacetamide 100104

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyridinylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 692.3 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyridinylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100105

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyridinylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 692.3 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyridinylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100106

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-((3S)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 696.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-((3R)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-((3S)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-((3R)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100107

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1- pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 711.8 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1- pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100108

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1- pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 711.8 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1- pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100109

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-((3S)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 695.9 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-((3R)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-((3S)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-((3R)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100110

2-methyl-2-propanyl (2R)-2- ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)propanoate 726.8 OR OR

2-methyl-2-propanyl (2R)-2- ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)propanoate OR OR

2-methyl-2-propanyl (2S)-2- ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)propanoate OR OR

2-methyl-2-propanyl (2S)-2- ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)propanoate 100111

2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N-diethylacetamide 713.9 OR OR

2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N-diethylacetamide 100112

2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N-diethylacetamide 713.9 OR OR

2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N-diethylacetamide 100113

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4- pyrimidinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 693.3 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4- pyrimidinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100114

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4- pyrimidinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 693.3 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4- pyrimidinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100115

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,2″-[1,3]oxathiolan]-15′-one 13′,13′-dioxide 659.3 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,2″-[1,3]oxathiolan]-15′-one 13′,13′-dioxide 100116

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,2″-[1,3]oxathiolan]-15′-one 13′,13′-dioxide 659.3 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,2″-[1,3]oxathiolan]-15′-one 13′,13′-dioxide 100117

(2R)-2-((1S,3′R,6′R,7′R,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide 700.4 OR OR

(2R)-2-((1S,3′R,6′R,7′S,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide OR OR

(2S)-2-((1S,3′R,6′R,7′R,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide OR OR

(2S)-2-((1S,3′R,6′R,7′S,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide 100118

(2R)-2-((1S,3′R,6′R,7′R,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide 700.4 OR OR

(2R)-2-((1S,3′R,6′R,7′S,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide OR OR

(2S)-2-((1S,3′R,6′R,7′R,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide OR OR

(2S)-2-((1S,3′R,6′R,7′S,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide 100119

(2R)-2-((1S,3′R,6′R,7′R,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide 700.4 OR OR

(2R)-2-((1S,3′R,6′R,7′S,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide OR OR

(2S)-2-((1S,3′R,6′R,7′R,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide OR OR

(2S)-2-((1S,3′R,6′R,7′S,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylpropanamide 100120

(2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid 670.8 OR OR

(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid OR OR

(2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid OR OR

(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid 100121

(2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid 670.8 OR OR

(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid OR OR

(2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid OR OR

(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid 100122

(2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid 670.8 OR OR

(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid OR OR

(2S)-24(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid OR OR

(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid 100123

(2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid 670.8 OR OR

(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid OR OR

(2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid OR OR

(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)propanoic acid 100124

(2R)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-dimethylpropanamide 697.7 OR OR

(2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylpropanamide OR OR

(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylpropanamide OR OR

(2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylpropanamide 100125

(2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylpropanamide 698.2 OR OR

(2R)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylpropanamide OR OR

(2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylpropanamide OR OR

(2R)-2-((1S,3′R,6′R,7′R,8′E,1l′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylpropanamide 100126

(2R)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylpropanamide 698.2 OR OR

(2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylpropanamide OR OR

(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylpropanamide OR OR

(2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylpropanamide 100127

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(2-propen- 1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 639.3 AND AND

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(2-propen- 1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100128

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-7′-(3-hydroxypropyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 657.4 AND AND

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-7′-(3-hydroxypropyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100129

(2S,3′R,4S,6′R,11′S,12′R,22′S)-6″-chloro- 4,11′,12′-trimethyl-3,3″,4,4″-tetrahydro- 2″H,5H,15′H-dispiro[furan-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalene]-5,15′-dione 13′,13′-dioxide 669.2 AND AND

(2R,3′R,4S,6′R,11′S,12′R,22′S)-6″-chloro- 4,11′,12′-trimethyl-3,3″,4,4″-tetrahydro- 2″H,5H,15′H-dispiro[furan-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalene]-5,15′-dione 13′,13′-dioxide 100130

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(2-propen- 1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 639.0 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(2-propen- 1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100131

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(2-propen- 1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 639.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(2-propen- 1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100132

(2S,3′R,6′R,8′E,11′S,12′R,22′S)-6″- chloro-11′,12′-dimethyl-3″,4,4″,5- tetrahydro-2″H,3H,15′H- dispiro[furan-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene-22′,1″-naphthalen]- 15′-one 13′,13′-dioxide 639.3 AND AND

(2R,3′R,6′R,8′E,11′S,12′R,22′S)-6″- chloro-11′,12′-dimethyl-3″,4,4″,5- tetrahydro-2″H,3H,15′H- dispiro[furan-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide 100133

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 645.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100134

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-3″- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,4″H,15′H-dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,5″-[1,2]oxazol]-15′-one 13′,13′-dioxide 670.1 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-3″- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,4″H,15′H-dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,5″-[1,2]oxazol]-15′-one 13′,13′-dioxide 100135

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-dimethylacetamide 720.2 OR OR

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N-dimethylacetamide 100136

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-3″- (dimethylamino)-11′,12′-dimethyl-3,4- dihydro-2H,4″H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,5″-[1,2]oxazol]-15′-one 13′,13′-dioxide 683.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-3″- (dimethylamino)-11′,12′-dimethyl-3,4- dihydro-2H,4″H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,5″-[1,2]oxazol]-15′-one 13′,13′-dioxide 100137

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-((3S)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 696.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-((3R)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-((3S)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-((3R)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100138

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(((4-methyl- 1-piperazinyl)sulfonyl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 777.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(((4-methyl- 1-piperazinyl)sulfonyl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100139

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(((4-methyl- 1-piperazinyl)sulfonyl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 777.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(((4-methyl- 1-piperazinyl)sulfonyl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100140

2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-(2-methoxyethyl)-N- methylacetamide 730.2 OR OR

2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-(2-methoxyethyl)-N- methylacetamide 100141

2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-(2-methoxyethyl)-N- methylacetamide 730.2 OR OR

2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-(2-methoxyethyl)-N- methylacetamide 100142

2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-methyl-N-(2-methyl-2- propanyl)acetamide 728.3 OR OR

2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-methyl-N-(2-methyl-2- propanyl)acetamide 100143

2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-methyl-N-(2-methyl-2- propanyl)acetamide 728.2 OR OR

2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-methyl-N-(2-methyl-2- propanyl)acetamide 100144

(1S,3′R,6′R,7′R,11′S,12′R)-7′-(2-(1- azetidinyl)-2-oxoethyl)-6-chloro-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 698.5 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-7′-(2-(1- azetidinyl)-2-oxoethyl)-6-chloro-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100145

(1S,3′R,6′R,7′R,11′S,12′R)-7′-(2-(1- azetidinyl)-2-oxoethyl)-6-chloro-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 698.5 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-7′-(2-(1- azetidinyl)-2-oxoethyl)-6-chloro-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100146

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyrimidinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 693.2 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyrimidinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100147

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro- 11′,12′-dimethyl-3″-(1-pyrrolidinyl)-3,4- dihydro-2H,4″H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,5″-[1,2]oxazol]-15′-one 13′,13′-dioxide 709.1 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro- 11′,12′-dimethyl-3″-(1-pyrrolidinyl)-3,4- dihydro-2H,4″H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,5″-[1,2]oxazol]-15′-one 13′,13′-dioxide 100148

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-7′-(3-hydroxypropyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 657.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-7′-(3-hydroxypropyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100149

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 645.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100150

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 645.2 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100151

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(4- pyrimidinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 691.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(4- pyrimidinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100152

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(4- pyrimidinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 691.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(4- pyrimidinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100153

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(2- oxo-1,3-oxazolidin-3-yl)ethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 728.5 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(2- oxo-1,3-oxazolidin-3-yl)ethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100154

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(2- oxo-1,3-oxazolidin-3-yl)ethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 728.5 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(2- oxo-1,3 -oxazolidin-3-yl)ethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100155

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-3″- ((2-methoxyethyl)(methyl)amino)- 11′,12′-dimethyl-3,4-dihydro- 2H,4″H,15′H-dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,5″-[1,2]oxazol]- 15′-one 13′,13′-dioxide 727.1 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-3″- ((2-methoxyethyl)(methyl)amino)- 11′,12′-dimethyl-3,4-dihydro- 2H,4″H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,5″-[1,2]oxazol]- 15′-one 13′,13′-dioxide 100156

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-7′-(3-hydroxypropyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 657.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-7′-(3-hydroxypropyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100157

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-7′-(3- buten-1-yl)-6-chloro-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 653.0 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-(3- buten-1-yl)-6-chloro-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100158

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-7′-(3- buten-1-yl)-6-chloro-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 653.0 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-(3- buten-1-yl)-6-chloro-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100159

(2S,3′R,6′R,8′E,11′S,12′R,22′S)-6″- chloro-11′,12′-dimethyl-3″,4,4″,5- tetrahydro-2″H,3H,15′H- dispiro[furan-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide 639.3 OR OR

(2R,3′R,6′R,8′E,11′S,12′R,22′S)-6″- chloro-11′,12′-dimethyl-3″,4,4″,5- tetrahydro-2″H,3H,15′H- dispiro[furan-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide 100160

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-7′-(3-methoxypropyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 671.4 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-7′-(3-methoxypropyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100161

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′- ((methylsulfonyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 693.2 AND AND

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′- ((methylsulfonyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100162

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((1-methyl- 1H-imidazol-2-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 695.5 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((1-methyl- 1H-imidazol-2-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100163

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((1-methyl- 1H-imidazol-2-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 695.5 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((1-methyl- 1H-imidazol-2-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100164

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,2″-oxiran]-15′-one 13′,13′-dioxide 613.2 AND AND

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,2″-oxiran]-15′-one 13′,13′-dioxide 100165

1-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene]-7′-yl)-N-(2-methoxyethyl)-N- methylmethanesulfonamide 766.2 OR OR

1-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-(2-methoxyethyl)-N- methylmethanesulfonamide 100166

1-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-(2-methoxyethyl)-N- methylmethanesulfonamide 766.3 OR OR

1-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-(2-methoxyethyl)-N- methylmethanesulfonamide 100167

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-(4- methyl-1-piperazinyl)-2-oxoethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 741.2 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-(4- methyl-1-piperazinyl)-2-oxoethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100168

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-(4- methyl-1-piperazinyl)-2-oxoethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 741.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-(4- methyl-1-piperazinyl)-2-oxoethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100169

1-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-methyl-N-(2-methyl-2- propanyl)methanesulfonamide 764.2 OR OR

1-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-methyl-N-(2-methyl-2- propanyl)methanesulfonamide 100170

1-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-methyl-N-(2-methyl-2- propanyl)methanesulfonamide 764.2 OR OR

1-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-methyl-N-(2-methyl-2- propanyl)methanesulfonamide 100171

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetaldehyde 641.5 OR OR

((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetaldehyde 100172

((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N- dimethylethanethioamide 702.1 OR OR

((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N- dimethylethanethioamide 100173

((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N- dimethylethanethioamide 702.1 OR OR

((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N- dimethylethanethioamide 100174

2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-4- pyrimidinylacetamide 736.2 OR OR

2-(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N-4- pyrimidinylacetamide 100175

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-7′-(2-hydroxyethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 643.4 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-7′-(2-hydroxyethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100176

2-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylacetamide 700.2 OR OR

2-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)-N,N-dimethylacetamide 100177

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-(3-hydroxypropyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 671.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-(3-hydroxypropyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100178

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-(3-hydroxypropyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 671.0 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-(3-hydroxypropyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100179

(2S,3′R,6′R,11′S,12′R,22′S)-6″-chloro- 11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,4-dioxane-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide 657.2 OR OR

(2R,3′R,6′R,11′S,12′R,22′S)-6″-chloro- 11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,4-dioxane-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide 100180

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(2- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 676.0 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11,12-dimethyl-7′-(2- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100181

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(2- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 676.0 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(2- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100182

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-7′,11′,12′-trimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 613.1 100183

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(3- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 676.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(3- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100184

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 645.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100185

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 678.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100186

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl- 1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 679.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl- 1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100187

4-(((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)methyl)-2- pyridinecarbonitrile 715.3 OR OR

4-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)methyl)-2- pyridinecarbonitrile 100188

4-(((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)methyl)-2- pyridinecarbonitrile 715.3 OR OR

4-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)methyl)-2- pyridinecarbonitrile 100189

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- methoxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 659.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- methoxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100190

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- (ethoxymethyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 659.2 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- (ethoxymethyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100191

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-7′-(6-methoxy-2-pyridinyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 706.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-7′-(6-methoxy-2-pyridinyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100192

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-7′((2-methoxyethoxy)methyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 689.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-7′-((2-methoxyethoxy)methyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100193

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-7′-((2-methoxyethoxy)methyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 689.2 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-7′-((2-methoxyethoxy)methyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100194

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- ((2-(dimethylamino)ethoxy)methyl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 702.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- ((2-(dimethylamino)ethoxy)methyl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100195

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- ((2-(dimethylamino)ethoxy)methyl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 702.2 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- ((2-(dimethylamino)ethoxy)methyl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100196

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- ((2-(dimethylamino)ethoxy)methyl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 702.2 AND AND

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- ((2-(dimethylamino)ethoxy)methyl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100197

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-3″- (dimethylamino)-11′,12′-dimethyl-3,4- dihydro-2H,4″H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,5″-[1,2]oxazol]- 15′-one 13′,13′-dioxide 683.2 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-3″- (dimethylamino)-11′,12′-dimethyl-3,4- dihydro-2H,4″H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,5″-[1,2]oxazol]-15′-one 13′,13′-dioxide 100198

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl- 1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 679.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl- 1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100199

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl- 1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 679.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(1-methyl- 1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100200

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-7′-(3-(hydroxymethyl)-1- methyl-1H-1,2,4-triazol-5-yl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 710.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-7′-(3-(hydroxymethyl)-1- methyl-1H-1,2,4-triazol-5-yl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100201

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(3-(hydroxymethyl)-1-methyl- 1H-1,2,4-triazol-5-yl)-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]- 15′-one 13′,13′-dioxide 710.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(3-(hydroxymethyl)-1-methyl- 1H-1,2,4-triazol-5-yl)-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′- one 13′,13′-dioxide 100202

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((3S)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 698.1 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((3S)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((3R)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((3R)-1- methyl-2-oxo-3-pyrrolidinyl)- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100203

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((3S)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 698.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((3S)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((3R)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((3R)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100204

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((3S)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 698.1 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((3S)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((3R)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((3R)-1- methyl-2-oxo-3-pyrrolidinyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100205

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((2S)-4- methyl-3-oxo-2-morpholinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 714.1 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((2R)-4- methyl-3-oxo-2-morpholinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((2S)-4- methyl-3-oxo-2-morpholinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((2R)-4- methyl-3-oxo-2-morpholinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100206

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- ethyl-7′-hydroxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 627.2 100207

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ethyl-7′-hydroxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 627.2 100208

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- propanyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 641.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- propanyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100209

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-propyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 641.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-propyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100210

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- propanyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 641.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- propanyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide 100211

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- methoxy-7′,11′,12′-trimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 629.3 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- methoxy-7′,11′,12′-trimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100212

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- methoxy-7′,11′,12′-trimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 629.3 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- methoxy-7′,11′,12′-trimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100213

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- cyclopropyl-7′-hydroxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 639.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- cyclopropyl-7′-hydroxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100214

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- cyclopropyl-7′-hydroxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 639.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- cyclopropyl-7′-hydroxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100215

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-7,11′,12′-trimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 627.2 100216

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro- 11′,12′-dimethyl-3″-(4-methyl-1- piperazinyl)-3,4-dihydro-2H,4″H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,5″-[1,2]oxazol]-15′-one 13′,13′-dioxide 738.0 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro- 11′,12′-dimethyl-3″-(4-methyl-1- piperazinyl)-3,4-dihydro-2H,4″H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,5″-[1,2]oxazol]-15′-one 13′,13′-dioxide 100217

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (2-hydroxyethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 657.2 100218

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-hydroxyethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 657.1 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (2-hydroxyethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100219

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-hydroxyethyl)-7′-methoxy-11′,12′,14′- trimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 671.1 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (2-hydroxyethyl)-7′-methoxy-11′,12′,14′- trimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100220

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- methylpropyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 655.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- methylpropyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100221

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1-methyl- 1H-1,2,4-triazol-5-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 680.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1-methyl- 1H-1,2,4-triazol-5-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100222

(1S,3′R,6′S,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1-methyl- 1H-1,2,4-triazol-5-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 680.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1-methyl- 1H-1,2,4-triazol-5-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100223

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1-methyl- 1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 681.2 100224

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- methylpropyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 655.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- methylpropyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100225

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- methoxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 659.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- methoxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100226

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1-methyl- 1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 681.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1-methyl- 1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100227

(2r,3′R,5R,6′R,11′S,12′R,22′S)-6″-chloro- 5-(dimethylamino)-11′,12′-dimethyl- 3″,4″-dihydro-2″H,15′H- dispiro[1,3-dioxane-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalen]- 15′-one 13′,13′-dioxide 700.1 AND AND

(2s,3′R,5S,6′R,11′S,12′R,22′S)-6″-chloro- 5-(dimethylamino)-11′,12′-dimethyl- 3″,4″-dihydro-2″H,15′H- dispiro[1,3-dioxane-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide 100228

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,2″-oxetan]-15′-one 13′,13′-dioxide 627.2 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,2″-oxetan]-15′-one 13′,13′-dioxide 100229

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,2″-oxetan]-15′-one 13′,13′-dioxide 627.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,2″-oxetan]-15′-one 13′,13′-dioxide 100230

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(1-methyl- 1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 695.3 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(1-methyl- 1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100231

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(hydroxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 629.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(hydroxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100232

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-propyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 641.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-propyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100233

(2S,3′R,6′R,8′E,11′S,12′R,22′S)-6″-chloro- 11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,4-dioxane-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene-22′,1″-naphthalen]- 15′-one 13′,13′-dioxide 655.2 OR OR

(2R,3′R,6′R,8′E,11′S,12′R,22′S)-6″-chloro- 11′,12′-dimethyl-3″,4″- dihydro-2″H,15′H- dispiro[1,4-dioxane-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide 100234

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ethyl-7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 641.2 100235

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-15′-oxo-3,4- dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene]-7′-carbonitrile 13′,13′-dioxide 624.1 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-15′-oxo-3,4- dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene]-7′-carbonitrile 13′,13′-dioxide 100236

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7-propyl-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 655.2 OR OR

(1S,3′R,6′R,7′R,8′E,115,12′R)-6-chloro-7- methoxy-11′,12′-dimethyl-7′-propyl-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100237

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-15′-oxo-3,4- dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene]-7′-carbonitrile 13′,13′-dioxide 624.1 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-15′-oxo-3,4- dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene]-7′-carbonitrile 13′,13′-dioxide 100238

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- (1,3-dithian-2-yl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 719.3 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- (1,3-dithian-2-yl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100239

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(1H-1,2,3- triazol-4-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 666.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(1H-1,2,3- triazol-4-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100240

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′- ((trimethylsilyl)ethynyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.4 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′- ((trimethylsilyl)ethynyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100241

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyridinylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 690.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyridinylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthale1e-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100242

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyridinylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 690.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyridinylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100243

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′- ((trimethylsilyl)ethynyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.4 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′- ((trimethylsilyl)ethynyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100244

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ethynyl-7′-hydroxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 623.5 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- ethynyl-7′-hydroxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100245

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1,3-thiazol- 2-ylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 696.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1,3-thiazol- 2-ylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100246

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1,3-thiazol- 2-ylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 696.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1,3-thiazol- 2-ylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100247

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-methyl-N- phenylacetamide 746.3 OR OR

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-methyl-N- phenylacetamide 100248

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-methyl-N- phenylacetamide 746.3 OR OR

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-methyl-N- phenylacetamide 100249

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- (1,3-dithian-2-yl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 733.4 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- (1,3-dithian-2-yl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100250

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1,3-thiazol- 2-ylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 698.3 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1,3-thiazol- 2-ylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100251

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1,3-thiazol- 2-ylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 698.3 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1,3-thiazol- 2-ylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100252

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1- pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 710.2 100253

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1- pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 710.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1- pyrrolidinyl)ethyl)-3,4-dihydro-2H,15 ′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100254

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- (1,3-dithian-2-yl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24~] trien]-15′-one 13′,13′-dioxide 733.3 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- (1,3-dithian-2-yl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100255

N-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- cyano-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)benzamide 729.2 OR OR

N-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- cyano-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)benzamide 100256

N-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)benzamide 734.2 OR OR

N-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)benzamide 100257

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1- piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 724.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1- piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100258

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1- piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 724.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-oxo-2-(1- piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100259

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (1,3-dithian-2-yl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 717.0 100260

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (1,3-dithian-2-yl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 717.2 100261

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (1,3-dithian-2-yl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 731.5 100262

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(hydroxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 629.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(hydroxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100263

N-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- cyano-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)acetamide 667.2 OR OR

N-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- cyano-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)acetamide 100264

(2S,3′R,6′R,8′E,11′S,12′R,22′S)-6″-chloro- 11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,4-dioxane-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide 655.2 OR OR

(2R,3′R,6′R,8′E,11′S,12′R,22′S)-6″-chloro- 11′,12′-dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[1,4-dioxane-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide 100265

N-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)acetamide 672.2 OR OR

N-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)acetamide 100266

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-propen-1- yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 641.2 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-propen-1- yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100267

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1-propyn-1- yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 639.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1-propyn-1- yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100268

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1-propyn-1- yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 639.3 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1-propyn-1- yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100269

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0-19,24~] pentacosa[16,18,24] triene-7′,3″-[1,4]oxazinan]-15′-one 13′,13′-dioxide 656.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- dispiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-7′,3″-[1,4] oxazinan]-15′-one 13′,13′-dioxide 100270

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 679.2 AND AND

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100271

((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)methyl methanesulfonate 709.1 OR OR

((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)methyl methanesulfonate 100272

N-((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro- 11′,12′-dimethyl-7′-(4- morpholinylmethyl)-13′,13′-dioxido-15′- oxo-3,4-dihydro-2H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)acetamide 741.2 OR OR

N-((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro- 11′,12′-dimethyl-7′-(4- morpholinylmethyl)-13′,13′- dioxido-15′- oxo-3,4-dihydro-2H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)acetamide 100273

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-propen-1- yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 641.3 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-propen-1- yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100274

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 677.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100275

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 677.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100276

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 693.3 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100277

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-(2- methoxyethyl)-N-methylacetamide 728.2 OR OR

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-(2-methoxyethyl)-N- methylacetamide 100278

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 691.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100279

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 679.2 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100280

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-11′,12′-dimethyl-7′-(2- (4-morpholinyl)ethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 744.3 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-11′,12′-dimethyl-7′-(2- (4-morpholinyl)ethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100281

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-(2- (dimethylamino)ethyl)-N- methylacetamide 741.2 OR OR

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-(2- (dimethylamino)ethyl)-N- methylacetamide 100282

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-(2- (dimethylamino)ethyl)-N- methylacetamide 741.3 OR OR

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-(2- (dimethylamino)ethyl)-N- methylacetamide 100283

((1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)methyl methanesulfonate 709.1 OR OR

((1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-7′-yl)methyl methanesulfonate 100284

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-11′,12′-dimethyl-7′-(2- (4-morpholinyl)ethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 744.3 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-11′,12′-dimethyl-7′-(2- (4-morpholinyl)ethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100285

(2R)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2-methoxy-N,N- dimethylethanamide 714.2 OR OR

(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2-methoxy-N,N- dimethylethanamide OR OR

(2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2-methoxy-N,N- dimethylethanamide OR OR

(2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2-methoxy-N,N- dimethylethanamide 100286

(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2-methoxy-N,N- dimethylethanamide 714.2 OR OR

(2R)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2-methoxy-N,N- dimethylethanamide OR OR

(2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2-methoxy-N,N- dimethylethanamide OR OR

(2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2-methoxy-N,N- dimethylethanamide 100287

methyl ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetate 671.2 100288

methyl ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetate 671.2 100289

(2R)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2-hydroxy-N,N- dimethylethanamide 700.3 OR OR

(2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2-hydroxy-N,N- dimethylethanamide OR OR

(2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2-hydroxy-N,N- dimethylacetamide OR OR

(2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2-hydroxy-N,N- dimethylethanamide 100290

(2S)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2-hydroxy-N,N- dimethylethanamide 700.3 OR OR

(2R)-2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2-hydroxy-N,N- dimethylethanamide OR OR

(2S)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2-hydroxy-N,N- dimethylethanamide OR OR

(2R)-2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2-hydroxy-N,N- dimethylethanamide 100291

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-15-oxo-3,4- dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene]-7′-carbaldehyde 13′,13′-dioxide 627.3 100292

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-7′-(2-(1- azetidinyl)-2-oxoethyl)-6-chloro-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 696.2 100293

1-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylmethanesulfonamide 720.2 OR OR

1-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylmethanesulfonamide 100294

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (3-(dimethylamino)-1-propyn-1-yl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 680.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (3-(dimethylamino)-1-propyn-1-yl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100295

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (3-(dimethylamino)-1-propyn-1-yl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 680.5 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (3-(dimethylamino)-1-propyn-1-yl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100296

(1S,3′R,6′R,75,8′E,11′S,12′R)-7′-(2-(1- azetidinyl)-2-oxoethyl)-6-chloro-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 696.2 100297

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-(3,3-difluoro-1-azetidinyl)-2-oxoethyl)- 7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 732.2 100298

(3-methyl-3-oxetanyl)methyl ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetate 741.2 OR OR

(3-methyl-3-oxetanyl)methyl ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetate 100299

(3-methyl-3-oxetanyl)methyl ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-13′,13′-dioxido- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetate 741.2 OR OR

(3-methyl-3-oxetanyl)methyl ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetate 100300

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- ((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-ylmethyl)-7,11′,12′- trimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 753.3 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- ((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-ylmethyl)-7′,11′,12′- trimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100301

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-7′,11′,12′-trimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 629.4 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-7′,11′,12′-trimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100302

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro- 7′,11′,12′-trimethyl-7′-(4- morpholinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 698.5 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro- 7′,11′,12′-trimethyl-7′-(4- morpholinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100303

(1R,2R,3′R,6′R,11′S,12′R,22′S)-6″-chloro- 2-((9aR)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-ylcarbonyl)-11′,12′- dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[cyclopropane-1,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide 779.3 OR OR

(1R,2S,3′R,6′R,11′S,12′R,22′S)-6″-chloro- 2-((9aR)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-ylcarbonyl)-11′,12′- dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[cyclopropane-1,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide 100304

(1R,2R,3′R,6′R,11′S,12′R,22′S)-6″-chloro- 2-((9aR)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-ylcarbonyl)-11′,12′- dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[cyclopropane-1,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalen]- 15′-one 13′,13′-dioxide 779.3 OR OR

(1R,2S,3′R,6′R,11′S,12′R,22′S)-6″-chloro- 2-((9aR)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-ylcarbonyl)-11′,12′- dimethyl-3″,4″-dihydro-2″H,15′H- dispiro[cyclopropane-1,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalen]-15′-one 13′,13′-dioxide 100305

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-yl)-2-oxoethyl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 781.2 100306

((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetic acid 671.2 100307

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetic acid 671.2 100308

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (4-(dimethylamino)-1-butyn-1-yl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.5 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (4-(dimethylamino)-1-butyn-1-yl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100309

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (4-(dimethylamino)-1-butyn-1-yl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.5 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (4-(dimethylamino)-1-butyn-1-yl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100310

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-11′,12′-dimethyl-7′-(2-(4- morpholinyl)ethoxy)-13′,13′-dioxido-15′- oxo-3,4-dihydro-2H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylacetamide 797.3 OR OR

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 11′,12′-dimethyl-7′-(2-(4- morpholinyl)ethoxy)-13′,13′-dioxido-15′- oxo-3,4-dihydro-2H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- dimethylacetamide 100311

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-((9aR)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-yl)-2-oxoethyl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 781.2 100312

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 643.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100313

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (2-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100314

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (2-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100315

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((2- propanylsulfonyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 733.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((2- propanylsulfonyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100316

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((2- propanylsulfonyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 733.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((2- propanylsulfonyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100317

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (2-((3R)-3-(dimethylamino)-1- pyrrolidinyl)-2-oxoethyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 767.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-((3R)-3-(dimethylamino)-1- pyrrolidinyl)-2-oxoethyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14,7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100318

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-((3R)-3-(dimethylamino)-1- pyrrolidinyl)-2-oxoethyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 767.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (2-((3R)-3-(dimethylamino)-1- pyrrolidinyl)-2-oxoethyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100319

(1S,3′R,6′R,7′S,11′S,12′R)-7′-benzyl-6- chloro-7′-hydroxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 691.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-7′-benzyl-6- chloro-7′-hydroxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100320

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3-(4- morpholinyl)-1-propyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 722.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3-(4- morpholinyl)-1-propyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100321

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 690.0 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100322

((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetaldehyde 655.2 100323

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetaldehyde 655.2 100324

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (2-fluoro-3-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 707.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-fluoro-3-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100325

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (2-fluoro-3-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 707.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-fluoro-3-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100326

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2R)-2-hydroxy-3-methylbutyl)-7- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 699.2 AND AND

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-((2S)-2-hydroxy-3-methylbutyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100327

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4-(4- morpholinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 736.4 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4-(4- morpholinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100328

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- (cis-5-(dimethylamino)-1,3-dioxan-2-yl)- 7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 728.3 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- (cis-5-(dimethylamino)-1,3-dioxan-2-yl)- 7′,11′,12′-trimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100329

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-((R)- methylsulfinyl)ethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 691.3 AND AND

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-((S)- methylsulfinyl)ethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-((R)- methylsulfinyl)ethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide AND AND

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-((S)- methylsulfinyl)ethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100330

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-((R)- methylsulfinyl)ethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 691.3 AND AND

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-((S)- methylsulfinyl)ethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-((R)- methylsulfinyl)ethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide AND AND

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-((S)- methylsulfinyl)ethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100331

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (6-fluoro-2-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.0 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (6-fluoro-2-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100332

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(1-propyn- 1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 653.3 100333

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(2-methoxy-3-pyridinyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 706.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(2-methoxy-3-pyridinyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100334

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(2-methoxy-3-pyridinyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 706.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(2-methoxy-3-pyridinyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100335

((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)methyl methanesulfonate 707.2 OR OR

((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)methyl methanesulfonate 100336

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro- 11′,12′-dimethyl-7′-(4- morpholinylmethyl)-15′-oxo-3,4- dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene]-7′-carbaldehyde 13′,13′-dioxide 712.5 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro- 11′,12′-dimethyl-7′-(4- morpholinylmethyl)-15′-oxo-3,4- dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene]-7′-carbaldehyde 13′,13′-dioxide 100337

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro- 11′,12′-dimethyl-7′-(4- morpholinylmethyl)-15′-oxo-3,4- dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene]-7′-carbaldehyde 13′,13′-dioxide 712.5 AND AND

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro- 11′,12′-dimethyl-7′-(4- morpholinylmethyl)-15′-oxo-3,4- dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene]-7′-carbaldehyde 13′,13′-dioxide 100338

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-15′-oxo-3,4- dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene]-7′-carbaldehyde 13′,13′-dioxide 629.2 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-15′-oxo-3,4- dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene]-7′-carbaldehyde 13′,13′-dioxide 100339

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (6-fluoro-2-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 676.0 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (6-fluoro-2-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100340

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (6-fluoro-2-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 676.0 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (6-fluoro-2-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100341

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-11′,12′-dimethyl-7′-(4- morpholinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 714.3 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-11′,12′-dimethyl-7′-(4- morpholinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100342

(1S,3′R,6′R,11′S,12′R)-6-chloro-7′,7′- bis(hydroxymethyl)-11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 645.2 100343

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-7′-(3-methoxy-1-propyn-1-yl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 681.5 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-7′-(3-methoxy-1-propyn-1-yl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100344

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (3-hydroxy-1-propyn-1-yl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 667.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (3-hydroxy-1-propyn-1-yl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100345

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (3-hydroxy-1-propyn-1-yl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 667.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (3-hydroxy-1-propyn-1-yl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100346

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((4,4-dimethyl-4,5-dihydro-1,3-oxazol-2- yl)methyl)-7′-hydroxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15-one 13′,13′- dioxide|(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-((4,4-dimethyl-4,5-dihydro-1,3- oxazol-2-yl)methyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 710.0 AND AND

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- ((4,4-dimethyl-4,5-dihydro-1,3-oxazol-2- yl)methyl)-7′-hydroxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′- dioxide|(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-((4,4-dimethyl-4,5-dihydro-1,3- oxazol-2-yl)methyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100347

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N,N- diethylacetamide 748.2 100348

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3- pyridazinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 677.0 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3- pyridazinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100349

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3- pyridazinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 677.0 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3- pyridazinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100350

3-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-1- methylpyridazin-1-ium 705.0 100351

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)ethyl methanesulfonate 757.1 (M + Na) 100352

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-7′-(2-methoxy-3-pyridinyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 720.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-7′-(2-methoxy-3-pyridinyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100353

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3-(4- morpholinyl)-1-propyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 724.3 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3-(4- morpholinyl)-1-propyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100354

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3-(4- morpholinyl)-1-propyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 724.3 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3-(4- morpholinyl)-1-propyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100355

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((2-(4- morpholinyl)ethoxy)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 742.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((2-(4- morpholinyl)ethoxy)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100356

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((2-(4- morpholinyl)ethoxy)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 742.3 OR OR

(1S,3′R,6′S,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((2-(4- morpholinyl)ethoxy)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100357

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyrazinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 677.0 100358

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- ((2S)-2-hydroxy-3-methylbutyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 721.5 (M + Na) OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- ((2R)-2-hydroxy-3-methylbutyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100359

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- ((2S)-2-hydroxy-3-methylbutyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 721.5 (M + Na) OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- ((2R)-2-hydroxy-3-methylbutyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100360

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 677.0 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100361

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 677.0 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100362

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(6-methoxy-3-pyridinyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 706.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(6-methoxy-3-pyridinyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100363

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(3-methyl- 2-oxobutyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 697.2 100364

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)ethyl methanesulfonate 757.2 (M + Na) 100365

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2-(4- morpholinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 726.3 100366

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2R)-2-hydroxy-3-methylbutyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 721.3 (M + Na) OR OR

|(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-((2S)-2-hydroxy-3-methylbutyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100367

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2R)-2-hydroxy-3-methylbutyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 721.3 (M + Na) OR OR

|(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-((2S)-2-hydroxy-3-methylbutyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100368

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (3-fluoro-4-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.0 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (3-fluoro-4-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100369

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-7′-(2-methoxyethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 671.2 100370

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (3-fluoro-4-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.0 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (3-fluoro-4-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100371

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4-(4- morpholinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 738.3 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4-(4- morpholinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100372

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4-(4- morpholinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 738.5 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4-(4- morpholinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100373

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(3-methyl- 2-oxobutyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 719.3 (M + Na) 100374

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N- cyclopropyl-N- methylacetamide 746.3 100375

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-methyl-N-(2,2,2- trifluoroethyl)acetamide 788.3 (M + Na) 100376

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2-(4- methyl-1-piperazinyl)-2-oxoethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 753.3 (M + Na) 100377

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-methyl-N-(2-(4- morpholinyl)ethyl)acetamide 797.3 100378

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 643.2 100379

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2- pyrazinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 659.0 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2- pyrazinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100380

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- ((4,4-dimethyl-4,5-dihydro-1,3-oxazol-2- yl)methyl)-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 724.2 100381

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (2-(dimethylamino)ethyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 684.3 100382

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1-methyl-4- piperidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 698.3 AND AND

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1-methyl-4- piperidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100383

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyrazinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 677.0 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyrazinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100384

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 676.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100385

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (3-fluoro-2-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (3-fluoro-2-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100386

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1-methyl-4- piperidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 698.3 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1-methyl-4- piperidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100387

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1-methyl-4- piperidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 698.3 OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1-methyl-4- piperidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100388

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (3-(1,1-dioxido-4-thiomorpholinyl)-1- propyn-1-yl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 770.4 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (3-(1,1-dioxido-4-thiomorpholinyl)-1- propyn-1-yl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100389

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (3-(1,1-dioxido-4-thiomorpholinyl)-1- propyn-1-yl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 770.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (3-(1,1-dioxido-4-thiomorpholinyl)-1- propyn-1-yl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100390

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (3-fluoro-2-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (3-fluoro-2-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100391

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(3- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 690.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(3- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100392

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 676.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100393

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-(dimethylamino)ethyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 684.2 100394

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(3-hydroxy-1-propyn-1-yl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 653.5 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(3-hydroxy-1-propyn-1-yl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100395

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(3-hydroxy-1-propyn-1-yl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 653.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(3-hydroxy-1-propyn-1-yl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100396

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-(1- (methoxymethyl)cyclopropyl)-N- methylacetamide 790.3 (M + Na) 100397

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2-propen- 1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 653.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2-propen- 1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100398

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(((3R)-1- methyl-3-piperidinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 712.4 AND AND

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(((3S)-1- methyl-3-piperidinyl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(((3R)-1- methyl-3-piperidinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide AND AND

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(((3S)-1- methyl-3-piperidiny)methy)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100399

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(((3R)-1- methyl-3-piperidinyl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 712.4 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(((3S)-1- methyl-3-piperidinyl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(((3R)-1- methyl-3-piperidinyl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(((3S)-1- methyl-3-piperidinyl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100400

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(((3S)-1- methyl-3-piperidinyl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 712.4 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(((3R)-1- methyl-3-piperidinyl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(((3R)-1- methyl-3-piperidinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(((3S)-1- methyl-3-piperidinyl)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100401

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 657.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100402

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (5-fluoro-2-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.0 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (5-fluoro-2-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100403

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (5-fluoro-2-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.0 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (5-fluoro-2-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100404

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-hydroxy-2-propanyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 671.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (2-hydroxy-2-propanyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100405

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N- cyclopentyl-N- methylacetamide 774.3 (M + Na) 100406

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-11′,12′-dimethyl-7′-(4- morpholinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 714.3 AND AND

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-11′,12′-dimethyl-7′-(4- morpholinylmethyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100407

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(6-methyl-3- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 690.0 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(6-methyl-3- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100408

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(6-methyl-3- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 690.0 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(6-methyl-3- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100409

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(3-(4- morpholinyl)-1-propyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 736.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(3-(4- morpholinyl)-1-propyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100410

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(5- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 677.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(5- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100411

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-((9aR)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-yl)-2-oxoethyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 795.2 100412

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2-(1- pyrrolidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 710.3 100413

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2,2-difluoro-N,N- dimethylacetamide 720.0 OR OR

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-2,2-difluoro-N,N- dimethylacetamide 100414

ethyl ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)(difluoro)acetate 721.0 OR OR

ethyl ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)(difluoro)acetate 100415

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2-(4- methyl-3-oxo-1-piperazinyl)ethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 775.3 (M + Na) 100416

ethyl ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)(difluoro)acetate 721.0 OR OR

ethyl ((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-hydroxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)(difluoro)acetate 100417

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-((2R)-2,4-dimethyl-1-piperazinyl)-2- oxoethyl)-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 789.3 (M + Na) AND AND

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-((2S)-2,4-dimethyl-1-piperazinyl)-2- oxoethyl)-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100418

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-(cyclopentyl(methyl)amino)ethyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 738.3 100419

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2-(4- morpholinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 726.3 100420

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (6-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 676.0 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (6-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100421

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3-(1- piperidinyl)-1-propyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 720.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3-(1- piperidinyl)-1-propyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100422

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(4-hydroxy-1-butyn-1-yl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 667.4 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(4-hydroxy-1-butyn-1-yl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100423

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-7′-(4-methoxy-1-butyn-1-yl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 695.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-7′-(4-methoxy-1-butyn-1-yl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100424

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3-(1- piperidinyl)-1-propyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 720.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3-(1- piperidinyl)-1-propyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100425

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (2-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-yl)ethyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 781.4 100426

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (4-hydroxy-1-butyn-1-yl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 681.3 100427

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (4-hydroxy-1-butyn-1-yl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 681.3 100428

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2-(1- piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 724.2 100429

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-yl)ethyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 781.4 100430

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2-(4- methyl-3-oxo-1-piperazinyl)ethyl)- 3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 753.3 100431

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-(3-(dimethylamino)-3-methyl-1- azetidinyl)ethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 753.3 100432

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3- (tetrahydro-2H-pyran-4-yl)-1-propyn-1- yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 721.3 100433

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(3- (tetrahydro-2H-pyran-4-yl)-1-propyn-1- yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 721.3 100434

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(5- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 677.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(5- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100435

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2R)-2-hydroxypropyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 693.2 (M + Na) OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2S)-2-hydroxypropyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100436

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2R)-2-hydroxypropyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 693.2 (M + Na) OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2S)-2-hydroxypropyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100437

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2R)-2-cyclopropyl-2-hydroxyethyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 719.3 (M + Na) AND AND

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2S)-2-cyclopropyl-2-hydroxyethyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100438

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-7′-((2E)-2- buten-1-yl)-6-chloro-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 667.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-7′-((2E)-2- buten-1-yl)-6-chloro-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100439

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(5-methyl-2- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 690.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(5-methyl-2- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100440

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(4-(2- pyridinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 728.3 AND AND

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′-hydroxy-11′,12′-dimethyl-7′-(4-(2- pyridinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100441

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((2- propanylsulfanyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 723.2 (M + Na) 100442

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((2- propanyloxy)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 671.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((2- propanyloxy)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100443

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-cyclopropyl-2-oxoethyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 717.2 (M + Na) 100444

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-((2-methoxyethoxy)methyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 687.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-((2-methoxyethoxy)methyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100445

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-((2-methoxyethoxy)methyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 687.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-((2-methoxyethoxy)methyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100446

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2- oxopropyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 691.2 (M + Na) 100447

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(3-methyl- 2-buten-1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 681.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(3-methyl- 2-buten-1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100448

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(3-(4- morpholinyl)-1-propyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 736.3 100449

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2-(1- piperidinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 724.4 100450

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-cyclobutyl-N- methylacetamide 738.2 100451

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-((2R)-1- methoxy-2-propanyl)-N- methylacetamide 778.3 (M + Na) AND AND

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-((2S)- 1-methoxy-2- propanyl)-N-methylacetamide 100452

(1S,3′R,6′R,11′S,12′R)-6-chloro-11′,12′- dimethyl-7′,7′-bis(4- morpholinylmethyl)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 783.5 100453

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (2-(3-(dimethylamino)-3-methyl-1- azetidinyl)ethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 753.3 100454

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4-(2- pyridinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 728.3 100455

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(4-(2- pyridinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 710.3 (M − H₂O] 100456

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (4-(1,1-dioxido-4-thiomorpholinyl)-1- butyn-1-yl)-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 798.3 100457

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2- oxobutyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 705.2 (M + Na) 100458

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2-oxo-2- phenylethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 753.2 (M + Na) 100459

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′- ((methylsulfonyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 705.2 100460

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2R)-2-cyclopropyl-2-hydroxyethyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 697.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2S)-2-cyclopropyl-2-hydroxyethyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100461

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2R)-2-cyclopropyl-2-hydroxyethyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 719.3 (M + Na) OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2S)-2-cyclopropyl-2-hydroxyethyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100462

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2S)-2-cyclopropyl-2-methoxyethyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 711.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2R)-2-cyclopropyl-2-methoxyethyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100463

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2S)-2-cyclopropyl-2-methoxyethyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 733.3 (M + Na) OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2R)-2-cyclopropyl-2-methoxyethyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100464

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-7′-(methoxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 657.2 100465

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-(2- hydroxyethyl)acetamide 682.0 (M − OMe) 100466

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-methoxyethoxy)-7′,11′,12′-trimethyl- 3,4-dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 671.3 100467

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 7′,11′,12′-trimethyl-7′-(2-(4- morpholinyl)ethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 726.3 100468

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(5- pyrimidinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 691.2 100469

(1S,3′R,6′R,7′R,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 678.2 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100470

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2S)-2-hydroxy-3-methyl-3-buten-1-yl)- 7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 697.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2R)-2-hydroxy-3-methyl-3-buten-1-yl)- 7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100471

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2S)-2-hydroxy-3-methyl-3-buten-1-yl)- 7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 697.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2R)-2-hydroxy-3-methyl-3-buten-1-yl)- 7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100472

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′-(2- (dimethylamino)ethyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 686.3 100473

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-7′-((1R)-1-methoxyethyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 671.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-7′-((1S)-1-methoxyethyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100474

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- ((3,5-difluorobenzyl)oxy)-7′,11′,12′- trimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 739.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((3,5-difluorobenzyl)oxy)-7′,11′,12′- trimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100475

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-7′-((1R)-1-methoxyethyl)- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 671.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-7′-((1S)-1-methoxyethyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100476

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(3-methyl- 2-oxo-3-buten-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 695.3 100477

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′,11′,12′-trimethyl-7′-(tetrahydro-2H- pyran-4-ylmethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 711.3 100478

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((3R)-4-(dimethylamino)-3-methyl-2- oxobutyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 740.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((3S)-4-(dimethylamino)-3-methyl-2- oxobutyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100479

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-((2R)-2,4-dimethyl-1-piperazinyl)-2- oxoethyl)-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 767.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-((2S)-2,4-dimethyl-1-piperazinyl)-2- oxoethyl)-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100480

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-((2S)-2,4-dimethyl-1-piperazinyl)-2- oxoethyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 767.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-((2R)-2,4-dimethyl-1-piperazinyl)-2- oxoethyl)-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100481

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- ethyl-11′,12′-dimethyl-7′-(2-(4- morpholinyl)ethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 740.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ethyl-11′,12′-dimethyl-7′-(2-(4- morpholinyl)ethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100482

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- ((1S)-1-hydroxyethyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 659.2 OR OR

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- ((1R)-1-hydroxyethyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 100483

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- ((1R)-1-hydroxyethyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 659.2 OR

100484

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-(3,3-difluoro-1-azetidinyl)ethoxy)- 7′,11′,12′-trimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 732.2 100485

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-(4-(2-methoxyethyl)-1- piperazinyl)ethoxy)-7′,11′,12′- trimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 783.3 100486

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((1S)-1-hydroxyethyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 657.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-((1R)-1-hydroxyethyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100487

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((1R)-1-hydroxyethyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 657.3 AND AND

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((1S)-1-hydroxyethyl)-7′-methoxy- 11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100488

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′- dimethyl-7′-(4-(4- (methylsulfonyl)-1-piperazinyl)-1-butyn- 1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 827.2 100489

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2S)-2-hydroxy-2-(2-pyridinyl)ethyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 734.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2R)-2-hydroxy-2-(2-pyridinyl)ethyl)-7′- methoxy-11′,12′- dimethyl-3,4-dihydro- 2H,15′H-spiro [naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100490

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2S)-2-hydroxy-2-(2-pyridinyl)ethyl)-7′- methoxy-11′,12′- dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 734.3 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((2R)-2-hydroxy-2-(2-pyridinyl)ethyl)-7′- methoxy-11′,12′- dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100491

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2-oxo-2-(2- pyridinyl)ethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 754.2 (M + Na) 100492

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7- ((methylsulfonyl)methyl)- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 705.2 100493

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(5-(4- morpholinyl)-1-pentyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 750.3 100494

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(5-(4- morpholinyl)-1-pentyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 750.3 100495

(2R,3′R,3′R,6′R,11′S,12′R,22′S)-6″-chloro- 11′,12′-dimethyl-15′-oxo-3″,4″-dihydro- 2″H-dispiro[1,4-dioxane-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalene]-3- carbaldehyde 13′,13′-dioxide 685.3 OR OR

(2R,3S,3′R,6′R,11′S,12′R,22′S)-6″-chloro- 11′,12′-dimethyl-15′-oxo-3″,4″-dihydro- 2″H-dispiro[1,4-dioxane-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalene]-3- carbaldehyde 13′,13′-dioxide OR OR

(2S,3′R,3′R,6′R,11′S,12′R,22′S)-6″-chloro- 11′,12′-dimethyl-15′-oxo-3″,4″-dihydro- 2″H-dispiro[1,4-dioxane-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalene]-3- carbaldehyde 13′,13′-dioxide OR OR

(2S,3S,3′R,6′R,11′S,12′R,22′S)-6″-chloro- 11′,12′-dimethyl-15′-oxo-3″,4″-dihydro- 2″H-dispiro[1,4-dioxane-2,7′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] triene-22′,1″-naphthalene]-3- carbaldehyde 13′,13′-dioxide 100496

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((2-propen- 1-yloxy)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 669.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((2-propen- 1-yloxy)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100497

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(1,3- thiazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 696.0 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(1,3- thiazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100498

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1-propyn-1- yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 637.4 100499

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(1-propyn-1- yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 637.3 100500

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (4,5-dihydro-1,3-oxazol-2-ylmethyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 696.2 100501

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(1-propyn- 1-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 651.2 100502

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ethynyl-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 637.3 100503

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- ethynyl-7′-methoxy-11′,12′-dimethyl- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 637.3 100504

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ethynyl-11′,12′-dimethyl-7′-(2-(4- morpholinyl)ethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 736.2 100505

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- ethynyl-11′,12′-dimethyl-7′-(2-(4- morpholinyl)ethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 736.2 100506

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(4-((3S)-3- methyl-4-morpholinyl)-1-butyn-1-yl)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 764.2 100507

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (5-(dimethoxymethyl)-3-pyridinyl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 750.0 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (5-(dimethoxymethyl)-3-pyridinyl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100508

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(1,3-oxazol- 2-ylmethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.3 100509

N-(2-chloroethyl)-2- ((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetamide 754.2 (M + Na) 100510

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (5-(dimethoxymethyl)-3-pyridinyl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14,7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 750.0 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (5-(dimethoxymethyl)-3-pyridinyl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100511

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (5-(dimethoxymethyl)-3-pyridinyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 764.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (5-(dimethoxymethyl)-3-pyridinyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100512

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((5-methyl- 1,3,4-oxadiazol-2-yl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 709.2 100513

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (1,3-dithian-2-yl)-7′-hydroxy-12′-(2- methoxyethyl)-11′-methyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 761.0 100514

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (5-(dimethoxymethyl)-3-pyridinyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 764.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (5-(dimethoxymethyl)-3-pyridinyl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100515

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (1,3-dithian-2-yl)-7′-methoxy-12′-(2- methoxyethyl)-11′-methyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 775.1 100516

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(2-methyl- 1,3-thiazol-4-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 695.8 100517

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2-methyl- 1,3-thiazol-4-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 710.0 100518

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (3-((9aS)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-yl)-1-propyn-1-yl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 791.3 100519

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(4-(4- pyrimidinyl)-1-butyn-1-yl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 743.2 100520

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-12′-(2-methoxyethyl)-11′- methyl-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene]-7′-carbaldehyde 13′,13′-dioxide 685.1 100521

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(5-(4- morpholinylmethyl)-3-pyridinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′- dioxide|(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-methoxy-11′,12′-dimethyl-7′- (5-(4-morpholinylmethyl)-3-pyridinyl)- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 789.2 AND AND

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(5-(4- morpholinylmethyl)-3-pyridinyl)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′- dioxide|(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-methoxy-11′,12′-dimethyl-7′- (5-(4-morpholinylmethyl)-3-pyridinyl)- 3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100522

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(1,3- thiazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 696.0 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(1,3- thiazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100523

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((1-methyl- 1H-imidazol-2-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 693.0 100524

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((1-methyl- 1H-imidazol-2-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 693.0 100525

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′- (1,3-thiazol-2-ylmethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 710.0 100526

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((3-methyl- 2-pyrazinyl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 705.0 100527

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((4-methyl- 1,3-oxazol-2-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 708.2 100528

methyl N-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)- 6-chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro- 2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetyl)-D-alaninate 778.3 (M + Na) 100529

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((5-methyl- 1,3-oxazol-2-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 708.2 100530

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (6-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 676.0 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (6-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100531

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(((4R)-4- methyl-5-oxo-4,5-dihydro-1,3-oxazol-2- yl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 724.2 AND AND

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(((4S)-4- methyl-5-oxo-4,5-dihydro-1,3-oxazol-2- yl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100532

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((4-methyl- 2-pyridinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 704.0 100533

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((4-methyl- 2-pyridinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 704.0 100534

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(5-phenyl-3- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 752.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-(5-phenyl-3- pyridinyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100535

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (6-fluoro-3-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 676.0 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (6-fluoro-3-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100536

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (4-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.0 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (4-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100537

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (4-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′- dioxide|(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-(4-fluoro-3-pyridinyl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.0 AND AND

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (4-fluoro-3-pyridinyl)-7′-hydroxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′- dioxide|(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-(4-fluoro-3-pyridinyl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100538

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (4-fluoro-3-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 708.0 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (4-fluoro-3-pyridinyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100539

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (2-chloro-1-methyl-1H-imidazol-5-yl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 727.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-chloro-1-methyl-1H-imidazol-5-yl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100540

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((5-methyl- 1,2-oxazol-3-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.0 100541

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((5-methyl- 1,2-oxazol-3-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.0 100542

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((3-methyl- 2-pyridinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 718.0 100543

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (2-chloro-1-methyl-1H-imidazol-5-yl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 713.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-chloro-1-methyl-1H-imidazol-5-yl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100544

methyl N-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)- 6-chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetyl)-2- methylalaninate 738.2 (M − OMe) 100545

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-((3R)-2- oxotetrahydro-3-furanyl)acetamide 722.3 (M − OMe) AND AND

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-((3S)-2- oxotetrahydro-3-furanyl)acetamide 100546

N-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6- chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetyl)-2- methylalanine 724.2 (M − OMe) 100547

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((4,4-dimethyl-5-oxo-4,5-dihydro-1,3- oxazol-2-yl)methyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 738.2 100548

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((5-methyl- 1,2-oxazol-3-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 708.0 100549

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((5-oxo-4,5- dihydro-1,3-oxazol-2-yl)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 710.3 100550

methyl N-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)- 6-chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetyl)glycinate 710.3 (M − OMe) 100551

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-chloro-1-methyl-1H-imidazol-5-yl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 713.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (2-chloro-1-methyl-1H-imidazol-5-yl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100552

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((5-methyl- 1,2-oxazol-3-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 708.0 100553

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(1-methyl- 1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 693.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(1-methyl- 1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100554

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (5-((dimethylamino)methyl)-3-pyridinyl)- 7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 747.2 100555

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (1,2-dimethyl-1H-imidazol-5-yl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 693.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (1,2-dimethyl-1H-imidazol-5-yl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100556

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(1-methyl- 1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 693.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(1-methyl- 1H-imidazol-2-yl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100557

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(4-methoxy-3-pyridinyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 706.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′-(4-methoxy-3-pyridinyl)- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100558

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-chloro-1-methyl-1H-imidazol-5-yl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 727.1 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (2-chloro-1-methyl-1H-imidazol-5-yl)-7′- methoxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100559

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (1,2-dimethyl-1H-imidazol-5-yl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 693.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (1,2-dimethyl-1H-imidazol-5-yl)-7′- hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100560

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((4-methyl- 2-pyridinyl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 718.0 100561

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-((3R)-2- oxotetrahydro-3- furanyl)acetamide 722.2 (M − OMe) OR OR

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-((3S)-2- oxotetrahydro-3-furanyl)acetamide 100562

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-((3R)-2- oxotetrahydro-3-furanyl)acetamide 722.2 (M − OMe) OR OR

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-((3S)-2- oxotetrahydro-3-furanyl)acetamide 100563

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-((2R)-3,3,3-trifluoro- 2-hydroxypropyl)acetamide 750.2 (M − OMe) AND AND

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-((2S)-3,3,3- trifluoro-2- hydroxypropyl)acetamide 100564

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (2-fluoro-2-propen-1-yl)-7′-hydroxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 657.0 100565

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (2-fluoro-2-propen-1-yl)-7′-hydroxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 657.0 100566

(1S,3′R,6′R,7′S,8′E,10′S,11′S)-6-chloro-7′- (1,3-dithian-2-yl)-7′-hydroxy-10′,11′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 717.0 100567

(1S,3′R,6′R,7′S,8′E,10′S,11′S)-6-chloro-7′- (1,3-dithian-2-yl)-7′-methoxy-10′,11′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 731.0 100568

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (2-fluoro-2-propen-1-yl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 671.0 100569

(1S,3′R,6′R,7′R,8′E,10′S,11′S)-6-chloro-7′- (1,3-dithian-2-yl)-7′-methoxy-10′,11′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 731.0 100570

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((4-(hydroxymethyl)-1,3-oxazol-2- yl)methyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 724.2 100571

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-12′-(2-methoxyethyl)-11′- methyl-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene]-7′-carbaldehyde 13′,13′-dioxide 685.1 100572

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-11′,12′-dimethyl-7′-((4-methyl- 1,3-oxazol-5-yl)methyl)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 694.8 100573

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- ((4,5-dimethyl-1,2-oxazol-3-yl)methyl)- 7′-hydroxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 708.0 100574

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- ((4,5-dimethyl-1,2-oxazol-3-yl)methyl)- 7′-methoxy-11′,12′-dimethyl-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 722.0 100575

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-12′- benzyl-6-chloro-7′-methoxy-11′-methyl- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene]-7′-carbaldehyde 13′,13′-dioxide 717.5 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-12′- benzyl-6-chloro-7′-methoxy-11′-methyl- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene]-7′-carbaldehyde 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′S)-12′- benzyl-6-chloro-7′-methoxy-11′-methyl- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene]-7′-carbaldehyde 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12S)-12- benzyl-6-chloro-7′-methoxy-11′-methyl- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene]-7′-carbaldehyde 13′,13′-dioxide 100576

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2-oxo-2- (3H-[1,2,3]triazolo[4,5-b]pyridin-3- yloxy)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 789.2 100577

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)-N-(1,3-oxazol-2- ylmethyl)acetamide 719.3 (M − OMe) 100578

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((4,5-dimethyl-1,2-oxazol-3-yl)methyl)- 7′-hydroxy-11′,12′-dimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 708.0 100579

(1S,3′R,6′R,7′S,8′E,12′R)-6-chloro-7′-(1,3- dithian-2-yl)-12′-ethyl-7′-methoxy-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 731.2 OR OR

(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-7′-(1,3- dithian-2-yl)-12′-ethyl-7′-methoxy-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100580

(1S,3′R,6′R,7′S,8′E,12′R)-6-chloro-12′- ethyl-7′-methoxy-15′-oxo-3,4-dihydro- 2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene]-7′-carbaldehyde 13′,13′-dioxide 641.2 OR OR

(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′- ethyl-7′-methoxy-15′-oxo-3,4-dihydro- 2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene]-7′-carbaldehyde 13′,13′-dioxide 100581

methyl N-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)- 6-chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetyl)-D- allothreoninate 754.2 (M − OMe) 100582

methyl (2R)-2- ((((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetyl)amino)-3- oxobutanoate 752.2 (M − OMe) AND AND

methyl (2S)-2- ((((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetyl)amino)-3- oxobutanoate 100583

methyl 2-(((1S,3′R,6′R,7′S,8′E,11′S,12′R)- 6-chloro-7′-methoxy-11′,12′-dimethyl- 13′,13′-dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)methyl)-5-methyl-1,3- oxazole-4-carboxylate 766.3 100584

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((4-(hydroxymethyl)-5-methyl-1,3- oxazol-2-yl)methyl)-7′-methoxy-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 738.2 100585

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-7′-((4-(methoxymethyl)-5- methyl-1,3-oxazol-2-yl)methyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 752.3 100586

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ((4-((dimethylamino)methyl)-5-methyl- 1,3-oxazol-2-yl)methyl)-7′-methoxy- 11′,12′-dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 765.3 100587

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((5-methyl- 4-(4-morpholinylmethyl)-1,3-oxazol-2- yl)methyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 807.3 100588

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-12′- benzyl-6-chloro-7′-(hydroxymethyl)-7′- methoxy-11′-methyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 742.2 (M + Na) OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-12′- benzyl-6-chloro-7′-(hydroxymethyl)-7′- methoxy-11′-methyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′S)-12′- benzyl-6-chloro-7′-(hydroxymethyl)-7′- methoxy-11′-methyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- 20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′S)-12′- benzyl-6-chloro-7′-(hydroxymethyl)-7′- methoxy-11′-methyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100589

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-11′,12′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-7′-yl)acetamide 638.3 (M − OMe) 100590

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((2-(4- morpholinyl)ethoxy)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 756.2 100591

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2-((9aR)- octahydro-2H-pyrido[1,2-a]pyrazin-2- yl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 779.3 100592

(1S,3′R,6′R,7′S,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-(2-((9aR)- octahydro-2H-pyrido[1,2-a] pyrazin-2-yl)ethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[16,18,24] trien]-15′-one 13′,13′-dioxide 781.2 100593

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 12′-(2-hydroxyethyl)-7′-methoxy-7′,11′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 657.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 12′-(2-hydroxyethyl)-7′-methoxy-7′,11′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100594

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-11′,12′-dimethyl-7′-((2-(4- morpholinyl)ethoxy)methyl)-3,4- dihydro-2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 756.2 100595

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-7′,11′-dimethyl-12′-(2-(4- morpholinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 726.3 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-7′,11′-dimethyl-12′-(2-(4- morpholinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100596

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 12′-(2-hydroxyethyl)-7′-methoxy-7′,11′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 657.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 12′-(2-hydroxyethyl)-7′-methoxy-7′,11′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100597

(1S,3′R,6′R,7′S,8′E,12′R)-6-chloro-12′- ethyl-7′-methoxy-7′-((2-(4- morpholinyl)ethoxy)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 756.2 OR OR

(1S,3′R,6′R,7′R,8′E,12′R)-6-chloro-12′- ethyl-7′-methoxy-7-((2-(4- morpholinyl)ethoxy)methyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100598

2-((1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro- 7′-methoxy-7′,11′-dimethyl-13′,13′- dioxido-15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-12′-yl)ethyl methanesulfonate 703.3 (M − OMe) OR OR

2-((1S,3′R,6′R,7′R,8′E,11′S,12′R)-6- chloro-7′-methoxy-7′,11′-dimethyl- 13′,13′-dioxido-15′-oxo- 3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-12′-yl)ethyl methanesulfonate 100599

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- methoxy-7′,11′-dimethyl-12′-(2-(4- morpholinyl)ethyl)-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 726.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- methoxy-7′,11′-dimethyl-12′-(2-(4- morpholinyl)ethyl)-3,4- dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100600

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′,11′,12′-trimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 614.0 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′,11′,12′- trimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100601

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′,11′,12′- trimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 614.0 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- hydroxy-7′,11′,12′- trimethyl-3,4-dihydro- 2H,15′H-spiro[naphthalene- 1,22′- [20]oxa[13]thia[1,14,25] triazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 100602

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 11′,12′-dimethyl-15′-oxo-7′-propoxy-3,4- dihydro-2H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene]-7′-carbaldehyde 13′,13′-dioxide 669.3 100603

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro- 11′,12′-dimethyl-7′-(2-methylpropoxy)- 15′-oxo-3,4-dihydro-2H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraene]-7′-carbaldehyde 13′,13′-dioxide 683.3 100604

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-11′,12′-dimethyl-7′- (2,2,2-trifluoroethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 711.2 OR OR

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- (hydroxymethyl)-11′,12′-dimethyl-7′- (2,2,2-trifluoroethoxy)-3,4-dihydro- 2H,15′H-spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 641.2 100605

(1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′- ethyl-7′-(hydroxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide 641.2 OR OR

(1S,3′R,6′R,7′R,8′E,11′S,12′R)-6-chloro-7′- ethyl-7′-(hydroxymethyl)-11′,12′- dimethyl-3,4-dihydro-2H,15′H- spiro[naphthalene-1,22′- [20]oxa[13]thia[1,14] diazatetracyclo[14.7.2.0~3,6~.0~19,24~] pentacosa[8,16,18,24] tetraen]-15′-one 13′,13′-dioxide

General Synthesis of Intermediates

Step 1: tert-butyl (2-morpholinoethyl)carbamate

A 2-dram vial was charged with di-t-butyldicarbonate (0.459 mL, 2.000 mmol), a magnetic stir bar, and indium (III) chloride (4.42 mg, 0.020 mmol). 4-(2-Aminoethyl)morpholine (0.262 mL, 2 mmol) was then added to the stirring solution. After 1 min, the solution was diluted with EtOAc (2 mL). Water (3 mL) was added and the layers were partitioned. The organic layer was washed with water (2×5 mL), dried over MgSO₄, filtered, and concentrated to afford tert-butyl (2-morpholinoethyl)carbamate as a clear oil. The material was carried forward without further purification.

Step 2: N-methyl-2-morpholinoethanamine

A 125 mL three-neck flask with stir bar was heated with a heat gun under vacuum. Under a positive pressure of nitrogen, a reflux condenser was attached to the middle neck. The flask was charged with tetrahydrofuran (25.00 mL) and lithium aluminium hydride (2 M solution in THF, 0.84 mL, 20 mmol), tert-butyl (2-morpholinoethyl)carbamate (0.46 g, 2 mmol) was added as a solution in THF (8 mL) and the resulting homogenous mixture was heated to reflux for 18 h. The reaction mixture was cooled to 0° C. in an ice-water bath and quenched with sodium sulfate decahydrate. The resulting mixture was filtered through Celite, rinsing with THF. Concentration of the filtrate afforded N-methyl-2-morpholinoethanamine which was used without further purification.

Step 1. (R)-pent-4-en-2-yl 4-methylbenzenesulfonate

To a solution of vinyl magnesium bromide (226 g, 1722 mmol, 1.0 M in THF) was added to CuI (29.5 g, 155 mmol, 0.09 equiv) in THF (200 mL) at −40° C. The reaction mixture was stirred for 30 min followed by a cooled solution of (R)-2-methyloxirane (100 g, 1722 mmol) in THF (500 mL) was added drop wise at the same temperature. The resulting reaction mixture was stirred at −40° C. for 1 h. After the reaction was completed (monitored by TLC), triethylamine (261 g, 2583 mmol) was added at −40° C. After 30 min, cooled solution of p-toluene sulfonyl chloride (427 g, 2238 mmol) in THF (1000 mL) was added slowly to the reaction mixture at same temperature and stirred for 16 h at ambient temperature. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with 1.5 N HCl solution until pH 3.0. The resulting reaction mixture was filtered through celite pad, layers were separated and the aqueous layer was re-extracted with ethyl acetate (2×2000 mL). The combined organic layers were washed with water (800 mL), brine (500 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified on flash column chromatography (silica gel, 230-400 mesh) using 1% to 2% ethyl acetate in petroleum ether to provide (R)-pent-4-en-2-yl 4-methylbenzenesulfonate (207 g, 50% yield) as a colourless liquid. ¹H NMR (300 MHz, Chloroform-d) δ 7.83-7.75 (m, 2H), 7.37-7.31 (m, 2H), 5.69-5.52 (m, 1H), 5.09-5.04 (m, 1H), 5.01 (t, J=1.3 Hz, 1H), 4.65 (h, J=6.3 Hz, 1H), 2.45 (s, 3H), 2.37-2.22 (m, 2H), 1.26 (d, J=6.3 Hz, 3H).

Step 2: (S)—N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-1-sulfonamide

To a stirred solution of N,N-bis(4-methoxybenzyl)methanesulfonamide (207 g, 617 mmol) in THF (2000 mL) was added n-BuLi (321 mL, 802 mmol, 2.5 M in hexane) at −78° C. The resulting reaction mixture was stirred for 1 h at same temperature followed by (R)-pent-4-en-2-yl 4-methylbenzenesulfonate (206 g, 858 mmol) in THF (400 mL) was added dropwise at −78° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution, layers were separated and the aqueous layer was extracted with ethyl acetate (2×2000 mL). The combined organic layers were washed with water (1000 mL), brine (600 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh) using 2% to 4% ethyl acetate in petroleum ether to provide (S)—N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-1-sulfonamide (105 g, 42% yield) as a colourless liquid. ¹H NMR (400 MHz, Chloroform-d) δ 7.25-7.20 (m, 4H), 6.92-6.85 (m, 4H), 5.70 (ddt, J=17.2, 10.2, 7.1 Hz, 1H), 5.12-4.98 (m, 2H), 4.32-4.19 (m, 4H), 3.83 (s, 6H), 2.90-2.80 (m, 1H), 2.66-2.55 (m, 1H), 2.27-2.17 (m, 1H), 2.17-2.02 (m, 2H), 1.11 (d, J=6.7, 3H).

Step 3. (3S)-1-cyclobutyl-N,N-bis(4-methoxybenzyl)-3-methylhex-5-ene-2-sulfonamide

To a stirred solution of (S)—N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-1-sulfonamide (40 g, 99 mmol) in THF (400 mL) was added n-butyl lithium (86.73 mL, 139 mmol, 1.6 M in hexane) at −78° C. The reaction mixture was allowed to stir for 20 min at same temperature. (Bromomethyl)cyclobutane (59.1 g, 396 mmol) was added dropwise at same temperature and stirred for 30 min. The resulting reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution, layers were separated and the aqueous layer was extracted with ethyl acetate (2×400 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh) using 2% to 4% ethyl acetate in petroleum ether as an eluent to provide (3S)-1-cyclobutyl-N,N-bis(4-methoxybenzyl)-3-methylhex-5-ene-2-sulfonamide (33 g, 71% yield) as colourless liquid. ¹H NMR (300 MHz, Chloroform-d) δ 7.30-7.16 (m, 4H), 6.92-6.80 (m, 4H), 5.13-4.95 (m, 2H), 4.40-4.20 (m, 4H), 3.81 (s, 6H), 2.87-2.63 (m, 2H), 2.16-1.72 (m, 6H), 1.65-1.24 (m, 6H), 1.15-0.81 (m, 3H).

Step 4: (3S)-1-cyclobutyl-3-methylhex-5-ene-2-sulfonamide

To a stirred solution of (3S)-1-cyclobutyl-N,N-bis(4-methoxybenzyl)-3-methylhex-5-ene-2-sulfonamide (33 g, 70.0 mmol), anisole (33 mL) and TFA (33 mL) at 0° C. The resulting reaction mixture was heated to 40° C. for 16 h. After the reaction was complete (monitored by TLC), volatiles were removed under vacuum and the crude was purified by flash column chromatography (silica gel, 230-400 mesh) using 15% to 20% ethyl acetate in petroleum ether as an eluent to yield (3S)-1-cyclobutyl-3-methylhex-5-ene-2-sulfonamide which was further purified by HPLC [Column Sunfire C18 (250 mm×19 mm) 5 μm, 0.1% formic acid in water and acetonitrile, 90 mg/injection, ELSD detector, run time 35 min.] to provide (3S)-1-cyclobutyl-3-methylhex-5-ene-2-sulfonamide (10.3 g, 64% yield) as a colourless liquid. MS (ESI, −ve ion) m/z 230 (M−H)⁻. ¹H NMR (400 MHz, DMSO-d₆) δ 6.78 (d, J=9.1 Hz, 2H), 5.73 (tdd, J=12.4, 10.1, 6.5 Hz, 1H), 5.05 (tt, J=17.7, 4.5 Hz, 2H), 2.70-2.54 (m, 2H), 2.30 (p, J=7.1 Hz, 1H), 2.00 (dq, J=26.6, 7.3 Hz, 4H), 1.90-1.72 (m, 3H), 1.58 (dtt, J=26.6, 17.4, 8.5 Hz, 3H), 0.94 (ddd, J=14.1, 7.1, 2.1 Hz, 3H).

1-(But-2-yn-1-yl)piperazin-2-one

Step 1: tert-butyl 4-(but-2-yn-1-yl)-3-oxopiperazine-1-carboxylate

To a cooled (0° C.) slurry of 60% sodium hydride in mineral oil (0.600 g, 15.00 mmol) in THF (40 mL) was added a solution of 1-Boc-3-oxopiperazine (2.0 g, 9.99 mmol; Combi-Blocks, San Diego, Calif.) in N, N-dimethylformamide (10 mL). After complete addition the reaction was allowed to warm to room temperature for 30 min. The mixture was cooled to 0° C. and treated with 1-bromo-2-butyne (1.2 mL, 13.71 mmol). The reaction was allowed to warm to rt for 30 min. The reaction was quenched with saturated NH₄Cl solution, partitioned between EtOAc/brine and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure to give tert-butyl 4-(but-2-yn-1-yl)-3-oxopiperazine-1-carboxylate as a light-brown liquid.

Step 2: 1-(but-2-yn-1-yl)piperazin-2-one

To a room temperature solution of tert-butyl 4-(but-2-yn-1-yl)-3-oxopiperazine-1-carboxylate (2.52 g, 9.99 mmol) in DCM (40 mL) was added trifluoroacetic acid (10 mL, 135 mmol) via syringe. After 1 h the solvent was removed in vacuo and the residue was dissolved in DCM. The solution was loaded onto an Si-propylsulfonic acid (Silicycle) cartridge eluting with DCM, MeOH then 2 M NH₃ in MeOH to give 1-(but-2-yn-1-yl)piperazin-2-one (1.269 g, 83% yield) as a brown oil. ¹H NMR (400 MHz, CDCl₃) δ 4.20 (q, J=2.41 Hz, 2H), 3.52 (s, 2H), 3.42 (t, J=5.48 Hz, 2H), 3.12 (t, J=5.58 Hz, 2H), 1.81 (t, J=2.45 Hz, 3H).

The intermediates shown in the following Table 3 were prepared analogous to the method described above for 1-(but-2-yn-1-yl)piperazin-2-one.

TABLE 3 MS Data Starting Material Product Name (M + 1)⁺

1-(2-(2-methoxy- ethoxy)ethyl) piperazin-2-one 203.3

1-(2-(dimethyl- amino)ethyl) piperazin-2-one 172.1

1-(2-Morpholinoethyl)piperazin-2-one

Step 1: tert-butyl 4-(2-morpholinoethyl)-3-oxopiperazine-1-carboxylate

To a room temperature suspension of 1-boc-3-oxopiperazine (2.0 g, 9.99 mmol; Combi-Blocks, San Diego, Calif.), tetrabutylammonium bromide (0.620 g, 1.923 mmol) and potassium hydroxide (1.42 g, 25.3 mmol) in THF (25 mL) was added 4-(2-bromoethyl)morpholine hydrobromide (2.78 g, 10.11 mmol; Combi-Blocks, San Diego, Calif.) as a solid. After stirring at room temperature overnight the mixture was filtered and the filtrate was evaporated onto silica gel and purified by flash chromatography (Isco, (80 gram)) eluting with 2 M NH₃ in MeOH:CH₂Cl₂ (0:1-1:9) to give tert-butyl 4-(2-morpholinoethyl)-3-oxopiperazine-1-carboxylate (1.923 g, 61% yield) as a solid. MS (ESI, +ve ion) m/z 314.3 (M+1)⁺.

Step 2: 1-(2-morpholinoethyl)piperazin-2-one

To a room temperature solution of tert-butyl 4-(2-morpholinoethyl)-3-oxopiperazine-1-carboxylate (1.84 g, 5.87 mmol) in DCM (15 mL) was added trifluoroacetic acid (5 mL). After 3 h the solvent was removed under reduced pressure and the residue was dissolved in DCM and loaded onto a plug of Si-propylsulfonic acid (Silicycle) and the plug washed with 1:1 MeOH/DCM to 2 M NH₃ in MeOH/DCM. The fractions containing desired product were concentrated under reduced pressure to give 1-(2-morpholinoethyl)piperazin-2-one (1.52 g) as a yellow oil. MS (ESI, +ve ion) m/z 214.1 (M+1)⁺.

(2S,3S)-3-Methyl-1-phenylhex-5-ene-2-sulfonamide AND (2R,3S)-3-methyl-1-phenylhex-5-ene-2-sulfonamide

Step 1: (R)-pent-4-en-2-yl 4-methylbenzenesulfonate

To a solution of vinyl magnesium bromide (226 g, 1722 mmol, 1.0 M in THF) was added to CuI (29.5 g, 155 mmol) in THF (200 mL) at −40° C. The reaction mixture was stirred for 30 min followed by a cooled solution of (R)-2-methyloxirane (100 g, 1722 mmol) in THF (500 mL) was added drop wise at the same temperature. The resulting reaction mixture was stirred at −40° C. for 1 h. After the reaction was completed (monitored by TLC), triethylamine (261 g, 2583 mmol) was added at −40° C. After 30 min, cooled solution of p-toluene sulfonyl chloride (427 g, 2238 mmol) in THF (1000 mL) was added slowly to the reaction mixture at same temperature and stirred for 16 h at ambient temperature. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with 1.5 N HCl solution until pH 3.0. The resulting reaction mixture was filtered through celite pad, layers were separated and the aqueous layer was re-extracted with ethyl acetate (2×2000 mL). The combined organic layers were washed with water (800 mL), brine (500 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified on flash column chromatography (silica gel, 230-400 mesh) using 1% to 2% ethyl acetate in petroleum ether to provide (R)-pent-4-en-2-yl 4-methylbenzenesulfonate (207 g, 50% yield) as a colourless liquid. ¹H NMR (300 MHz, Chloroform-d) δ 7.83-7.75 (m, 2H), 7.37-7.31 (m, 2H), 5.69-5.52 (m, 1H), 5.09-5.04 (m, 1H), 5.01 (t, J=1.3 Hz, 1H), 4.65 (h, J=6.3 Hz, 1H), 2.45 (s, 3H), 2.37-2.22 (m, 2H), 1.26 (d, J=6.3 Hz, 3H).

Step 2: (S)—N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-1-sulfonamide

To a stirred solution of N,N-bis(4-methoxybenzyl)methanesulfonamide (207 g, 617 mmol, 1.0 equiv) in THF (2000 mL) was added n-BuLi (321 mL, 802 mmol, 2.5 M in hexane) at −78° C. The resulting reaction mixture was stirred for 1 h at same temperature followed by (R)-pent-4-en-2-yl 4-methylbenzenesulfonate (206 g, 858 mmol) in THF (400 mL) was added dropwise at −78° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution, layers were separated and the aqueous layer was extracted with ethyl acetate (2×2000 mL). The combined organic layers were washed with water (1000 mL), brine (600 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh) using 2% to 4% ethyl acetate in petroleum ether to provide (S)—N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-1-sulfonamide (105 g, 42.2% yield) as a colourless liquid. ¹H NMR (400 MHz, Chloroform-d) δ 7.25-7.20 (m, 4H), 6.92-6.85 (m, 4H), 5.70 (ddt, J=17.2, 10.2, 7.1 Hz, 1H), 5.12-4.98 (m, 2H), 4.32-4.19 (m, 4H), 3.83 (s, 6H), 2.90-2.80 (m, 1H), 2.66-2.55 (m, 1H), 2.27-2.17 (m, 1H), 2.17-2.02 (m, 2H), 1.11 (d, J=6.7, 3H).

Step 3: (2S,3S)—N,N-bis(4-methoxybenzyl)-3-methyl-1-phenylhex-5-ene-2-sulfonamide AND (2R,3 S)—N,N-bis(4-methoxybenzyl)-3-methyl-1-phenylhex-5-ene-2-sulfonamide

To a stirred solution of (S)—N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-1-sulfonamide (65 g, 161 mmol) in THF (650 mL) was added n-butyl lithium (140.9 mL, 226 mmol, 1.6 M in hexane) at −78° C. The reaction mixture was stirred for 20 min at same temperature. (Bromomethyl)benzene (110 g, 644 mmol) was added dropwise at same temperature and stirred for 30 min at −78° C. The resulting reaction mixture was warmed to ambient temperature and stirred for 1 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution, layers were separated and the aqueous layer was extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with water (300 mL), brine (100 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh) using 2% to 4% ethyl acetate in petroleum ether as an eluent to provide (2S,3S)—N,N-bis(4-methoxybenzyl)-3-methyl-1-phenylhex-5-ene-2-sulfonamide AND (2R,3S)—N,N-bis(4-methoxybenzyl)-3-methyl-1-phenylhex-5-ene-2-sulfonamide (60.5 g, 76% yield) as a colourless liquid. ¹H NMR (400 MHz, Chloroform-d) δ 7.28-7.14 (m, 7H), 7.02-6.92 (m, 2H), 6.90-6.84 (m, 4H), 5.60-5.52 (m, 1H), 5.04-4.82 (m, 2H), 4.54-4.32 (m, 2H), 4.10-3.96 (m, 2H), 3.84-3.80 (m, 6H), 3.28-3.12 (m, 2H), 2.98-2.88 (m, 1H), 2.42-2.08 (m, 1H), 2.00-1.76 (m, 2H), 1.18-1.04 (m, 3H).

Step 4: (2S,3S)-3-methyl-1-phenylhex-5-ene-2-sulfonamide AND (2R,3 S)-3-methyl-1-phenylhex-5-ene-2-sulfonamide

To a stirred solution of (2S,3S)—N,N-bis(4-methoxybenzyl)-3-methyl-1-phenylhex-5-ene-2-sulfonamide AND (2R,3S)—N,N-bis(4-methoxybenzyl)-3-methyl-1-phenylhex-5-ene-2-sulfonamide (60 g, 122 mmol) in anisole (99 g, 915 mmol) was added TFA (148 g, 1298 mmol) at 0° C. The resulting reaction mixture was heated to 40° C. for 16 h. After the reaction was completed (monitored by TLC), volatiles were removed under reduced pressure and the crude was purified by flash column chromatography (silica gel, 230-400 mesh) using 15% to 20% ethyl acetate in petroleum ether as an eluent to provide (2S,3S)-3-methyl-1-phenylhex-5-ene-2-sulfonamide AND (2R,3S)-3-methyl-1-phenylhex-5-ene-2-sulfonamide (21.5 g, 70% yield) as liquid. MS (ESI, −ve ion) m/z 254.2 (M−1)⁻. ¹H NMR (400 MHz, DMSO-d₆) δ 7.37-7.15 (m, 5H), 6.94-6.86 (m, 2H), 5.62-5.54 (m, 1H), 4.96-4.70 (m, 2H), 3.32-3.20 (m, 2H), 2.92-2.80 (m, 1H), 2.49-2.28 (m, 1H), 2.10-1.78 (m, 2H), 1.08-0.90 (m, 3H).

(2S,3S)-2,3-Dimethylpent-4-ene-1-sulfonamide

Step 1: meso-2,3-dimethylbutane-1,4-diol

A solution of meso-2,3-dimethylsuccinic acid (50.0 g, 342 mmol) in THF (700 mL) was cooled to 0° C. Lithium aluminum hydride (2.0 M solution in tetrahydrofuran, 428.0 mL, 855.0 mmol) was then cannulated into the addition funnel, and then added into the stirred cooled mixture dropwise over 15 min. After the addition was completed the reaction was allowed to warm to room temperature and stirred for 12 h under a nitrogen atmosphere. The reaction mixture was quenched with MeOH (350 mL) dropwise at 0° C. and then 20% KOH (150 mL) aqueous solution was added slowly. The reaction mixture was stirred at 0° C. for 20 min, EtOAc (1000 mL) was added and the organic phase was dried over MgSO₄ filtered and concentrated under reduced pressure to give meso-2,3-dimethylbutane-1,4-diol (40.0 g, 100% yield) which was used as such in next step. MS (ESI, +ve ion) m/z 119.2 (M+H)⁺.

Step 2: rac-(2R,3S)-4-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbutan-1-ol

To a suspension of sodium hydride (60% dispersion in mineral oil, 20.31 g, 508.0 mmol) in THF (1200 mL) at 0° C. under a N₂ atmosphere was added a solution of meso-2,3-dimethylbutane-1,4-diol (40.0 g, 338.0 mmol) in THF (200 mL) dropwise over 20 min. After addition, the reaction was heated at 55° C. for 45 min and cooled to 0° C. The reaction mixture was treated with a solution of tert-butyldimethylsilyl chloride (51.0 g, 338.0 mmol) in THF (200 mL). The reaction was stirred at room temperature for 12 h. The reaction was quenched by adding saturated NH₄Cl (500 mL) and diluted with EtOAc (500 mL). The separated aqueous layer was extracted with EtOAc (3×500 mL) and the combined organic extracts was washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure to give rac-(2R,3S)-4-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbutan-1-ol (70.0 g, 301.0 mmol, 89% yield) which was used as such in next step. MS (ESI, +ve ion) m/z 233.0 (M+H)⁺.

Step 3: rac-(2R,3S)-4-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbutanal

To a solution of rac-(2R,3 S)-4-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbutan-1-ol (70.0 g, 301.0 mmol) and (diacetoxyiodo)benzene (107.0 g, 301.0 mmol) in DCM (250 mL) was added 2,2,6,6-tetramethyl-1-piperidinyloxy (2.35 g, 15.06 mmol) in one portion at room temperature. The reaction mixture was stirred for 12 h at room temperature. The reaction mixture was poured into DCM (500 mL) and washed with saturated aqueous sodium bicarbonate solution (250 mL) and brine (250 mL). The organic layer was dried over MgSO₄, and concentrated under reduced pressure. The crude material was purified by column chromatography using silica gel 60-120 mesh, eluting with 0% to 10% EtOAc in hexane to give rac-(2R,3S)-4-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbutanal (45.0 g, 195.0 mmol, 64.7% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 3.51 (dd, J=10.1, 5.2 Hz, 1H), 3.40 (dd, J=10.0, 8.2 Hz, 1H), 2.35-2.22 (m, 2H), 0.94 (d, J=6.8 Hz, 3H), 0.90 (d, J=6.9 Hz, 3H), 0.83 (s, 9H). 0.03 (s, 3H) 0.01 (s, 3H). MS (ESI, +ve) m/z 231.2 (M+H)⁺.

Step 4: rac-(2S,3S)-2,3-dimethylpent-4-en-1-ol

A solution of methyl triphenylphosphonium bromide (185.0 g, 521.0 mmol) in THF (1500 mL) was treated with n-butyllithium (2.5 M solution in hexane, 174.0 mL, 18.8 mmol) at 0° C. After 10 min, the resulting yellow mixture was allowed to stir at room temperature for 20 min. A solution of rac-(2R,3S)-4-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbutanal (40.0 g, 174.0 mmol) in THF (50 mL) was added to the reaction mixture at −78° C. After 10 min, the reaction mixture was allowed to stirred at 0° C. for 2 h and then quenched with saturated aqueous NH₄Cl (500 mL) solution and water (200 mL). Diethylether (500 mL) was added and layers were separated. The aqueous layer was extracted with ether (3×500 mL). The combined organic layer was dried over MgSO₄, and concentrated under reduced pressure to get the crude material. The crude compound was dissolved in DCM (300 mL) and treated with 1.0 N HCl in diethylether (250 mL). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography using silica gel (60-120 mesh), eluting with 0% to 30% EtOAc in hexane to give rac-(2S,3S)-2,3-dimethylpent-4-en-1-ol (8.0 g, 70.1 mmol, 40.2% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 5.82-5.61 (m, 1H), 5.04-4.87 (m, 2H), 4.37 (t, J=5.2 Hz, 1H), 3.39-3.25 (m, 1H), 3.19 (ddd, J=10.5, 6.7, 5.2 Hz, 1H), 2.33-2.16 (m, 1H), 1.56-1.36 (m, 1H), 0.95 (d, J=6.9 Hz, 3H), 0.76 (d, J=6.9 Hz, 3H). MS (ESI, +ve) m/z 115.1 (M+H)⁺.

Step 5: rac-(2S,3S)-2,3-dimethylpent-4-en-1-yl methanesulfonate

To a solution of rac-(2S,3S)-2,3-dimethylpent-4-en-1-ol (5.0 g, 43.8 mmol) and triethylamine (13.43 mL, 96.0 mmol) in DCM (200 mL) was added methanesulfonyl chloride (5.12 mL, 65.7 mmol, 1.5 equiv) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. Then the reaction was quenched with saturated NH₄Cl (100 mL) solution and extracted with EtOAc (3×200 mL) and the combined organic extracts were washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure to give rac-(2S,3S)-2,3-dimethylpent-4-en-1-yl methanesulfonate which was used without further purification. MS (ESI, +ve) m/z 193.2 (M+H)⁺.

Step 6: rac-2-(((2S,3S)-2,3-dimethylpent-4-en-1-yl)thio)pyrimidine

A solution of 2-mercapto-pyrimidine (27.5 g, 245.0 mmol) and potassium carbonate (36.3 g, 263.0 mmol) in DMF (1000 mL) was stirred at room temperature for 10 min. A solution of rac-(2S,3S)-2,3-dimethylpent-4-en-1-yl methanesulfonate (337 g, 175.0 mmol) in THF (1000 mL) was added at room temperature. The resulting mixture was heated to 50° C. for 4 h and stirred at room temperature for 12 h. The crude mixture was quenched with cold water (500 mL) and extracted with EtOAc (3×500 mL). The combined organic layer was concentrated under reduced pressure. The crude material was purified by column chromatography (EtOAc/hexanes, 0% to 15%, silica gel) to give rac-2-(((2S,3S)-2,3-dimethylpent-4-en-1-yl)thio)pyrimidine (19.0 g, 91.0 mmol, 52% yield). ¹H NMR (300 MHz, Chloroform-d) δ 8.50 (d, J=4.7 Hz, 2H), 6.94 (t, J=4.8 Hz, 1H), 5.76 (ddd, J=16.8, 10.6, 8.2 Hz, 1H), 5.19-4.97 (m, 2H), 3.25 (dd, J=13.2, 5.9 Hz, 1H), 2.99 (dd, J=13.1, 7.9 Hz, 1H), 2.50-2.32 (m, 1H), 1.93-1.74 (m, 1H), 1.07 (d, J=6.8 Hz, 3H), 1.00 (d, J=6.9 Hz, 3H). MS (ESI, +ve) m/z 209.0 (M+H)⁺.

Step 7: rac-2-(((2S,3S)-2,3-dimethylpent-4-en-1-yl)sulfonyl)pyrimidine

To a solution of rac-2-(((2S,3S)-2,3-dimethylpent-4-en-1-yl)thio)pyrimidine (25.0 g, 120.0 mmol) in acetonitrile (500 mL) and water (50 mL) was added sodium tungstate dehydrate (7.92 g, 24.0 mmol) followed by hydrogen peroxide (61.3 mL, 600.0 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated sodium thiosulfate (750 mL). The reaction mixture was extracted with ethyl-acetate (3×1000 mL) and combined organic layer was dried over sodium-sulphate, filtered and concentrated under reduced pressure to give rac-2-(((2S,3S)-2,3-dimethylpent-4-en-1-yl)sulfonyl)pyrimidine (25.0 g, 104.0 mmol, 86% yield). ¹H NMR (400 MHz, Chloroform-d) δ 8.98 (d, J=4.8 Hz, 2H), 7.59 (t, J=4.9 Hz, 1H), 5.78-5.59 (m, 1H), 5.14-5.01 (m, 2H), 3.58 (dd, J=14.3, 4.0 Hz, 1H), 3.32 (dd, J=14.3, 8.5 Hz, 1H), 2.48-2.28 (m, 2H), 1.10 (d, J=6.8 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H). MS (ESI, +ve) m/z 241.2 (M+H)⁺.

Step 8: rac-(2S,3S)-2,3-dimethylpent-4-ene-1-sulfonamide

To a solution of rac-2-(((2S,3S)-2,3-dimethylpent-4-en-1-yl)sulfonyl)pyrimidine (25.0 g, 104.0 mmol) in methanol (500 mL) was added sodium methoxide (22.48 g, 104.0 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The crude mixture was diluted with water (500 mL) and washed with ethyl acetate (3×250 mL). Sodium acetate (10.24 g, 125 mmol) and hydroxylamine-o-sulfonic acid (14.12 g, 125 mmol) was added to the aqueous layer. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was extracted with MTBE (3×500 mL) and the combined organic layer was washed with saturated sodium carbonate (2×300 mL), dried over sodium-sulphate, filtered and concentrated under reduced pressure to give rac-(2S,3S)-2,3-dimethylpent-4-ene-1-sulfonamide (14.0 g, 79.0 mmol, 76% yield). ¹H NMR (400 MHz, Chloroform-d) δ 5.71 (ddd, J=17.8, 10.5, 7.2 Hz, 1H), 5.19-4.92 (m, 4H), 3.19 (dd, J=14.6, 3.7 Hz, 1H), 2.89 (dd, J=14.6, 8.3 Hz, 1H), 2.36 (q, J=6.2 Hz, 1H), 2.19 (th, J=7.5, 4.0, 3.3 Hz, 1H), 1.11 (dd, J=6.6, 2.9 Hz, 3H), 1.03 (dd, J=6.7, 2.9 Hz, 3H). MS (ESI, +ve) m/z 178.2 (M+H)⁺.

Step 1: (S)-tert-butyl 4-benzyl-2-(hydroxymethyl)piperazine-1-carboxylate

To a solution of (S)-1-boc-2-(hydroxymethyl)piperazine (5.0 g, 23.12 mmol) in 1,2-dichloroethane (100 mL) was added benzaldehyde (7.04 mL, 69.4 mmol). The resulting mixture was then stirred at room temperature for 30 min, and then sodium triacetoxyborohydride (6.85 mL, 46.2 mmol) was added. The resulting mixture was then stirred at room temperature overnight. Then, the mixture was quenched with saturated NaHCO₃ (20 mL) and was stirred at room temperature for 10 min. The organic layer was collected and aqueous layer was extracted with EtOAc (1×30 mL). The combined organic extracts were then dried over MgSO₄ and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc/heptane) provided (S)-tert-butyl 4-benzyl-2-(hydroxymethyl)piperazine-1-carboxylate (5.86 g, 19.13 mmol, 83% yield) as an oil. MS (ESI, +ve ion) m/z 307.3 (M+H)⁺.

Step 2: (S)-(4-benzylpiperazin-2-yl)methanol

To a solution of (S)-tert-butyl 4-benzyl-2-(hydroxymethyl)piperazine-1-carboxylate (5.86 g, 19.13 mmol) in DCM (30 mL) was added trifluoroacetic acid (11.37 mL, 153 mmol). After addition, the mixture was then stirred at room temperature for 2.5 h. Then, additional trifluoroacetic acid (7 mL) was added and the mixture was stirred at room temperature for an additional 1 h. Then, the mixture was concentrated in vacuo and H₂O (10 mL) was added. The mixture was then adjusted to pH=14 with NaOH (1 N). The mixture was then extracted with EtOAc (3×30 mL). The combined organic extracts were dried over MgSO₄, concentrated, and dried in vacuo at 40° C. overnight provided (S)-(4-benzylpiperazin-2-yl)methanol as an oil that was used without further purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.26-7.38 (5H, m) 3.62-3.81 (2H, m) 3.54 (2H, d, J=4.11 Hz) 3.25-3.35 (2H, m) 3.02-3.14 (1H, m) 2.77-2.90 (2H, m) 2.41 (1H, td, J=11.88, 2.45 Hz) 2.18-2.30 (1H, m). MS (ESI, +ve ion) m/z 207.1 (M+H)⁺.

Step 3: (S)-1-(4-benzyl-2-(hydroxymethyl)piperazin-1-yl)-2-chloroethanone

To a solution of (S)-(4-benzylpiperazin-2-yl)methanol (1.4 g, 6.79 mmol) and triethylamine (2.83 mL, 20.36 mmol) in DCM (5 mL) at 0° C. under N₂ was added chloroacetyl chloride (0.540 mL, 6.79 mmol) dropwise. After addition, the mixture was then stirred at 0° C. for 48 min. Then, MeOH (10 mL) was added and the mixture was concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc/heptane) provided (S)-1-(4-benzyl-2-(hydroxymethyl)piperazin-1-yl)-2-chloroethanone (530 mg, 1.874 mmol, 27.6% yield) as an oil. MS (ESI, +ve ion) m/z 283.1 (M+H)⁺.

Step 4: (S)-8-benzylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one

To a solution of (S)-1-(4-benzyl-2-(hydroxymethyl)piperazin-1-yl)-2-chloroethanone (530 mg, 1.874 mmol) in THF (40 mL) at 0° C. under N₂ was added potassium tert-butoxide (421 mg, 3.75 mmol). After addition, the mixture was stirred at 0° C. for 2 h. LCMS showed no starting material. Then, MeOH (10 mL) was added and the mixture was concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc/heptane) provided (S)-8-benzylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (262 mg, 1.064 mmol, 56.8% yield) as an oil. MS (ESI, +ve ion) m/z 247.1 (M+H)⁺.

Step 4: (S)-hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one

A solution of (S)-8-benzylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (262 mg, 1.064 mmol) and acetic acid (0.123 mL, 2.127 mmol) in methanol (2.5 mL) in a pressure vial was added a solution of palladium (5% on activated carbon, 34 mg, 0.319 mmol) in EtOAc (0.3 mL). Then, the mixture was degassed with hydrogen 5 times, and then was charged with hydrogen at 40 psi. The mixture was then stirred for 3.5 h. LCMS showed some starting material. Then, palladium (5% on activated wood carbon, 34 mg, 0.319 mmol) and acetic acid (0.123 mL, 2.127 mmol) were added. Then, the mixture was degassed 5 times with hydrogen, and then charged with hydrogen at 40 psi. The resulting mixture was stirred at room temperature overnight at 40 psi. Then, the mixture was filtered through celite and the celite was washed with MeOH/EtOAc 1:1 (2×3 mL). The combined filtrates were concentrated and dried in vacuo provided (S)-hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (166 mg, 1.063 mmol, 100% yield) as an oil, which was used without further purification. MS (ESI, +ve ion) m/z 157.1 (M+H)⁺.

(3S,9aS)-3-methylhexahy dropyrazino[2,1 -c][1,4]oxazin-4(3H)-one AND (3R,9aS)-3-methylhexahydropyrazinol[2,1-c][1,4]oxazin-4(3H)-one

Step 1: (S)-1-((S)-4-benzyl-2-(hydroxymethyl)piperazin-1-yl)-2-chloropropan-1-one AND (R)-1-((S)-4-benzyl-2-(hydroxymethyl)piperazin-1-yl)-2-chloropropan-1-one

To a solution of (S)-(4-benzylpiperazin-2-yl)methanol (1.4 g, 6.79 mmol) and triethylamine (2.83 mL, 20.36 mmol) in DCM (10 mL) at 0° C. was added 2-chloropropionyl chloride (0.862 mL, 6.79 mmol). After addition, the mixture was stirred at 0° C. for 2 h. LCMS showed no starting material. Then, MeOH (10 mL) was added and the mixture was concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc/heptane) provided (S)-1-((S)-4-benzyl-2-(hydroxymethyl)piperazin-1-yl)-2-chloropropan-1-one (176 mg, 0.593 mmol, 8.74% yield) as an oil and the first eluting isomer from the silica gel column. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.28-7.40 (5H, m) 4.46-4.73 (2H, m) 4.14 (1H, br s) 3.69-4.03 (3H, m) 3.41-3.63 (2H, m) 3.10 (1H, br s) 2.93 (1H, br s) 2.35 (1H, br s) 2.02-2.23 (1H, m) 1.65-1.69 (3H, m). MS (ESI, +ve ion) m/z 297.0 (M+H)⁺. In addition, (R)-1-((S)-4-benzyl-2-(hydroxymethyl)piperazin-1-yl)-2-chloropropan-1-one (142 mg, 0.478 mmol, 7.1% yield) was isolated as an oil and the second eluting isomer from the silica gel column. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.27-7.40 (5H, m), 4.60-4.72 (1H, m), 4.44-4.59 (1H, m), 3.97 (1H, d, J=4.30 Hz), 3.68-3.93 (3H, m), 3.51 (2H, d, J=18.58 Hz), 3.07 (1H, br s), 2.92 (1H, br s), 2.11-2.45 (2H, m), 1.64-1.73 (3H, m). MS (ESI, +ve ion) m/z 297.0 (M+H)⁺.

Step 2: (3S,9aS)-8-benzyl-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one

To a solution of (R)-1-((S)-4-benzyl-2-(hydroxymethyl)piperazin-1-yl)-2-chloropropan-1-one (142 mg, 0.478 mmol) in THF (50 mL) under nitrogen at 0° C. was added potassium tert-butoxide (59.1 mg, 0.526 mmol). The resulting mixture was then stirred at 0° C. for 1 h and at room temperature for 10 d. Then, MeOH (10 mL) was added and the mixture was concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc/heptane) provided (3S,9aS)-8-benzyl-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (33 mg, 0.127 mmol, 26.5% yield) as an oil. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ 7.11-7.28 (6H, m), 4.31-4.42 (1H, m), 4.02-4.10 (1H, m), 3.69-3.77 (1H, m), 3.54-3.63 (1H, m), 3.37-3.49 (3H, m), 2.63-2.80 (3H, m), 1.92-2.05 (2H, m), 1.31 (3H, d, J=6.85 Hz). MS (ESI, +ve ion) m/z 261.1 (M+H)⁺.

Step 3: (3S,9aS)-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one

To a solution of (3S,9aS)-8-benzyl-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (33 mg, 0.127 mmol) in methanol (0.5 mL) was added acetic acid (0.015 mL, 0.254 mmol) and palladium (10 wt % dry basis on activated carbon, wet, degussa type, 6.74 mg, 0.063 mmol). The resulting mixture was then purged with hydrogen, then was charged with hydrogen at 40 psi. The resulting mixture was then stirred at room temperature overnight. Then, the mixture was filtered through celite and the celite was washed with EtOAc (2×3 mL). The combined filtrates were concentrated in vacuo and chromatographic purification of the residue (silica gel, 0% to 50% MeOH/DCM) provided (3S,9aS)-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (20 mg, 0.118 mmol, 93% yield) as an oil. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ 4.43-4.58 (1H, m), 4.09-4.19 (1H, m), 3.86 (1H, dd, J=12.52, 4.50 Hz), 3.66-3.75 (1H, m), 3.53 (1H, td, J=7.53, 3.72 Hz), 2.97-3.12 (2H, m), 2.65-2.87 (3H, m), 1.41 (3H, d, J=6.85 Hz). MS (ESI, +ve ion) m/z 171.1 (M+H)⁺.

Step 4: (3R,9aS)-8-benzyl-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one

To a solution of (S)-1-((S)-4-benzyl-2-(hydroxymethyl)piperazin-1-yl)-2-chloropropan-1-one (176 mg, 0.593 mmol) in THF (50 mL) at 0° C. under nitrogen was added potassium tert-butoxide (100 mg, 0.890 mmol). After addition, the mixture was then stirred at 0° C. for 30 min. LCMS showed no starting material. Then, saturated NaHCO₃ (5 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were dried over MgSO₄, concentrated, and dried in vacuo provided (3R,9aS)-8-benzyl-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (154 mg, 0.592 mmol, 100% yield) as an oil, which was used without purification. MS (ESI, +ve ion) m/z 261.0 (M+H)⁺.

Step 5: (3R,9aS)-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one

To a solution of (3R,9aS)-8-benzyl-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (154 mg, 0.592 mmol) in methanol (2 mL) was added a solution of palladium (10 wt % dry basis on activated carbon, wet, degussa type, 18.89 mg, 0.177 mmol) in EtOAc (0.2 mL). The resulting mixture was then purged with hydrogen five times and charged with hydrogen at 40 psi. The resulting mixture was then stirred for 10 d. Then, the mixture was filtered through celite and the celite was washed with EtOAc (2×5 mL). The combined filtrates were concentrated. Chromatographic purification of the residue (silica gel, 0% to 20% MeOH/DCM) provided (3R,9aS)-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (93 mg, 0.546 mmol, 92% yield) as an oil. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 4.27-4.45 (1H, m), 4.05 (1H, q, J=6.85 Hz), 3.74 (1H, dd, J=12.23, 4.60 Hz), 3.54-3.63 (1H, m), 3.24-3.36 (1H, m), 2.84-2.91 (1H, m), 2.80 (1H, dd, J=11.74, 2.74 Hz), 2.50-2.67 (3H, m), 1.32 (3H, d, J=6.85 Hz). MS (ESI, +ve ion) m/z 171.1 (M+H)⁺.

To a solution of (3S,9aS)-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (52 mg, 0.306 mmol) in 1,4-dioxane (4 mL) at room temperature under nitrogen was added lithium aluminium hydride (2.0 M in THF, 1.22 mL, 2.44 mmol) dropwise. After addition, the mixture was then stirred at 80° C. for 6 h. Then, the mixture was quenched with 2-propanol (1 mL) at 0° C. followed by saturated Na₂SO₄ (3 mL). The mixture was then stirred at room temperature for 30 min and then was filtered. The filtered cake was washed with MeOH (2×5 mL). The combined filtrates were concentrated and dried in vacuo. The residue was then dissolved in MeOH (5 mL) and silica gel was added. The mixture was concentrated and dried in vacuo. The solid mixture was then purified by silica gel column chromatography using ISCO instrument (solid loading, 0% to 20% ammonia in MeOH 2 M/DCM) provided (3S,9aS)-3-methyloctahydropyrazino[2,1-c][1,4]oxazine (67 mg, 0.429 mmol, 140% yield) as a solid that contained residual solvent and was used without further purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ 3.94 (1H, dt, J=6.55, 3.37 Hz), 3.72 (1H, q, J=7.04 Hz), 3.52-3.59 (2H, m), 3.03-3.10 (2H, m), 2.86-2.96 (1H, m), 2.68-2.82 (5H, m), 1.90 (1H, br s), 1.34 (3H, d, J=6.65 Hz). MS (ESI, +ve ion) m/z 157.1 (M+H)⁺.

To a solution of (3R,9aS)-3-methylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (80 mg, 0.470 mmol) in 1,4-dioxane (5 mL) under N₂ at room temperature was added lithium aluminium hydride (1.0 M in THF, 1.88 mL, 1.88 mmol) dropwise. After addition, the mixture was stirred at 80° C. for 6 h. Then, the mixture was quenched 2-propanol (1 mL) at 0° C. followed by saturated Na₂SO₄ (3 mL). The mixture was then stirred at room temperature for 30 min and then was filtered. The filtered cake was washed with MeOH (2×5 mL). The combined filtrates were concentrated and dried in vacuo. The residue was then dissolved in MeOH (5 mL) and silica gel was added. The mixture was concentrated and dried in vacuo. The solid mixture was then purified by silica gel column chromatography using ISCO instrument (solid loading, 0% to 20% ammonia in MeOH 2 M/DCM) provided (3R,9aS)-3-methyloctahydropyrazino[2,1-c][1,4]oxazine (20 mg, 0.128 mmol, 27.2% yield) as an oil. ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ 3.92 (1H, ddd, J=6.50, 3.96, 2.25 Hz), 3.42-3.50 (1H, m), 3.30-3.37 (1H, m), 2.79-2.92 (2H, m), 2.53-2.68 (2H, m), 2.37-2.50 (3H, m), 2.06-2.24 (2H, m), 1.90 (1H, br s), 1.33 (3H, d, J=6.65 Hz). MS (ESI, +ve ion) m/z 157.2 (M+H)⁺.

Step 1: (R)-tert-butyl 2-((((benzyloxy)carbonyl)amino)methyl)piperidine-1-carboxylate

To a solution of (R)-tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (475 mg, 2.216 mmol) in DCM (5.0 mL) at 0° C. was added iPr₂Net (0.424 mL, 2.438 mmol) followed by benzyl chloroformate (0.693 mL, 2.438 mmol). The resulting mixture was then stirred at 0° C. for 2 h and at room temperature for 14 h. Then, saturated NaHCO₃ (30 mL) was added to the mixture and the mixture was stirred at room temperature for 3 min. The organic layer was collected and aqueous layer was extracted with EtOAc (1×20 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc/heptane) provided (R)-tert-butyl 2-((((benzyloxy)carbonyl)amino)methyl)piperidine-1-carboxylate (772 mg, 2.216 mmol, 100% yield) as an oil. MS (ESI, +ve ion) m/z 371.1 (M+Na)⁺.

Step 2: (R)-benzyl (piperidin-2-ylmethyl)carbamate

A solution of (R)-tert-butyl 2-((((benzyloxy)carbonyl)amino)methyl)piperidine-1-carboxylate (772 mg, 2.216 mmol) in DCM (5 mL) was added trifluoroacetic acid (1.646 mL, 22.16 mmol). The resulting mixture was then stirred at room temperature for 2 h. Then, iPr₂Net (3.85 mL, 22.16 mmol) was added dropwise to the mixture at 0° C. and the mixture was stirred at room temperature for 5 min. Then, the mixture was concentrated in vacuo and chromatographic purification of the residue (silica gel, 0% to 100% EtOH:EtOAc (3:1)/heptane) provided (R)-benzyl (piperidin-2-ylmethyl)carbamate (495 mg, 90% yield) as an oil. MS (ESI, +ve ion) m/z 249.2 (M+H)⁺.

Step 3: (R)-benzyl ((1-(2-chloroacetyl)piperidin-2-yl)methyl)carbamate

To a solution of (R)-benzyl (piperidin-2-ylmethyl)carbamate (150 mg, 0.604 mmol) in 1,2-dichloroethane (1 mL) and DCM (1 mL) at 0° C. under nitrogen was added iPr₂Net (0.168 mL, 0.966 mmol) followed by chloroacetyl chloride (0.063 mL, 0.785 mmol). After addition, the mixture was then stirred at 0° C. for 1 h. Then, the mixture was quenched with saturated NaHCO₃ (2.5 mL) and extracted with EtOAc (2×3 mL). The combined organic extracts were then dried over Na₂SO₄ and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc/heptane) provided (R)-benzyl ((1-(2-chloroacetyl)piperidin-2-yl)methyl)carbamate (126 mg, 0.388 mmol, 64.2% yield) as a solid. MS (ESI, +ve ion) m/z 325.1 (M+H)⁺.

Step 4: (R)-benzyl 4-oxohexahydro-1H-pyrido[1,2-a]pyrazine-2(6H)-carboxylate

To a solution of (R)-benzyl ((1-(2-chloroacetyl)piperidin-2-yl)methyl)carbamate (126 mg, 0.388 mmol) in tetrahydrofuran (5 mL) was added sodium hydride (60% dispersion in mineral oil, 31 mg, 0.776 mmol) in portions. After addition, the mixture was then stirred at room temperature for 5 h. Then, the mixture was carefully quenched with water (5 mL). The mixture was then extracted with EtOAc (2×10 mL). The combined organic extracts were then dried over Na₂SO₄ and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc/heptane) provided (R)-benzyl 4-oxohexahydro-1H-pyrido[1,2-a]pyrazine-2(6H)-carboxylate (112 mg, 0.388 mmol, 100% yield) as an oil. MS (ESI, +ve ion) m/z 289.1 (M+H)⁺.

Step 5: (R)-hexahydro-1H-pyrido[1,2-a]pyrazin-4(6H)-one

To a solution of (R)-benzyl 4-oxohexahydro-1H-pyrido[1,2-a]pyrazine-2(6H)-carboxylate (112 mg, 0.388 mmol) in ethanol (3 mL) was added ammonium formate (122 mg, 1.942 mmol) and 10% palladium on carbon (124 mg, 0.117 mmol). The resulting mixture was then stirred at 70° C. for 1 h. The mixture was filtered through celite and the filter cake was washed with a mixture of EtOAc and MeOH (1:1, 3×2 mL). The combined filtrates were concentrated and chromatographic purification of the residue (silica gel, 0% to 15% 2 M ammonia in MeOH/DCM) provided (R)-hexahydro-1H-pyrido[1,2-a]pyrazin-4(6H)-one (54 mg, 0.350 mmol, 90% yield) as an oil. MS (ESI, +ve ion) m/z 155.1 (M+H)⁺.

Step 1: tert-butyl 8-acetylhexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate

To stirred solution of tert-butyl hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (0.680 g, 2.82 mmol) in DCM (10 mL) was added at room temperature under argon diisopropylethylamine (1.078 mL, 6.20 mmol) followed by 2,5-dioxopyrrolidin-1-yl acetate (0.885 g, 5.64 mmol) in one portion as a solid. The resulting mixture was stirred at room temperature for 24 h. The crude mixture was directly loaded onto a silica gel precolumn (25 g), previously covered with a layer of sodium bicarbonate, and subjected to flash column chromatography on a 24 g ISCO gold column eluting with 0% to 3% MeOH/DCM to give tert-butyl 8-acetylhexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate as an oil. This was taken onto the next step without further purification. MS (ESI, +ve ion) m/z 306.4 (M+Na)⁺.

Step 2: 1-(dihydro-1H-pyrazino[1,2-a]pyrazin-2(6H,7H,8H,9H,9aH)-yl)ethanone

To a solution of tert-butyl 8-acetylhexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate in DCM (10 mL) was added 2,2,2-trifluoroacetic acid (2.0 mL) at room temperature. The resulting mixture was stirred at room temperature overnight and the volatiles were removed to give 1-(hexahydro-1H-pyrazino[1,2-a]pyrazin-2(6H)-yl)ethanone 2,2,2-trifluoroacetate as a solid which was used without further purification.

Step 1: tert-butyl 8-(methylsulfonyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate

To a stirred ice-cooled mixture of tert-butyl hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (1.000 g, 4.14 mmol) and diisopropylethylamine (1.442 mL, 8.29 mmol) in DCM (14 mL) was dropwise added methanesulfonyl chloride (0.385 mL, 4.97 mmol) via a syringe. The resulting mixture was stirred at 0° C. for 10 min and stirred at ambient temperature for 19 h. The volatiles were removed and the residue was loaded onto a silica gel precolumn (25 g) and subjected to combi-flash column chromatography on a 24 g ISCO gold column eluting with 0% to 100% MeOH/DCM to give tert-butyl 8-(methylsulfonyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (1.30 g, 4.07 mmol, 98% yield) as an oil. MS (ESI, +ve ion) m/z 320.1 (M+1)⁺.

Step 2: 2-(methylsulfonyl)octahydro-1H-pyrazino[1,2-a]pyrazine

To a stirred solution of tert-butyl 8-(methylsulfonyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (1.30 g, 4.07 mmol) in DCM (20 mL) was added 2,2,2-trifluoroacetic acid (2.0 mL, 4.14 mmol) via a syringe. The resulting mixture was stirred at room temperature for 2.5 h. Additional TFA (2×2.5 mL) was added over the first 2 h. The volatiles were removed in vacuo and the residue was subjected to high vacuum overnight to give 2.4 g of 2-(methylsulfonyl)octahydro-1H-pyrazino[1,2-a]pyrazine 2,2,2-trifluoroacetate as a solid which was used without further purification. MS (ESI, +ve ion) m/z 220.2 (M+1)⁺.

Step 1: tert-butyl 8-(3-(phenylsulfonyl)propanoyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate

To a stirred mixture of tert-butyl hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (0.46 g, 1.906 mmol) and 3-(phenylsulfonyl)propionic acid (0.490 g, 2.287 mmol) in DCM (6.5 mL) was added at room temperature iPr₂Net (0.829 mL, 4.77 mmol) via a syringe followed by HATU (1.450 g, 3.81 mmol) in one portion as a solid. The resulting mixture was stirred at room temperature for 75 min. The crude mixture was directly loaded onto a silica gel precolumn (25 g) and subjected to combi-flash column chromatography on a 24-g ISCO gold column eluting with 0% to 15% MeOH/DCM to give 1.28 g tert-butyl 8-(3-(phenylsulfonyl)propanoyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate as an oil which was taken onto the next step without further purification. MS (ESI, +ve ion) m/z 438.2 (M+1)⁺.

Step 2: 1-(dihydro-1H-pyrazino[1,2-a]pyrazin-2(6H,7H,8H,9H,9aH)-yl)-3-(phenylsulfonyl)propan-1-one

A mixture of tert-butyl 8-(3-(phenylsulfonyl)propanoyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (1.28 g, 2.93 mmol) and 2,2,2-trifluoroacetic acid (4.0 mL, 2.93 mmol) in DCM (15 mL) was stirred at room temperature for 50 min. The volatiles were removed and the residue was subjected to high vacuum overnight to give 1.5 g of 1-(dihydro-1H-pyrazino[1,2-a]pyrazin-2(6H,7H,8H,9H,9aH)-yl)-3-(phenylsulfonyl)propan-1-one as an oil that was used without further purification. MS (ESI, +ve ion) m/z 338.1 (M+1)⁺.

Step 1: tert-butyl 8-isopropylhexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate

A mixture of tert-butyl hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (0.53 g, 2.196 mmol) and acetone (0.806 mL, 10.98 mmol) in DCM (5.0 mL) was stirred at rt for 10 min before sodium triacetoxyhydroborate (2.327 g, 10.98 mmol) was added at room temperature in one portion as a solid. The resulting mixture was stirred at room temperature for 24 h. The reaction was quenched with MeOH (5 mL) and the resulting slurry was directly loaded onto a silica gel precolumn (25 g) and subjected to combi-flash column chromatography on a 12 g ISCO gold column eluting with 0% to 20% MeOH/DCM to give tert-butyl 8-isopropylhexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (0.65 g, 2.293 mmol, 104% yield) as an oil. MS (ESI, +ve ion) m/z 284.3 (M+1)⁺.

Step 2: 2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine

A mixture of tert-butyl 8-isopropylhexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (0.65 g, 2.293 mmol) and 2,2,2-trifluoroacetic acid (4.0 mL, 2.293 mmol) in DCM (15 mL) was stirred at room temperature for 2 h. The volatiles were removed in vacuo and the residue was subjected to high vacuum overnight to give 1.74 g of 2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine as an oil that was used without further purification. MS (ESI, +ve ion) m/z 184.2 (M+1)⁺.

The title compound was synthesized, from (1R,4R)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (AstaTech, Inc.), similarly using the protocol in the synthesis of 2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine. MS (ESI, +ve ion) m/z 141.2 (M+1)⁺.

The title compound was synthesized, from (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (AstaTech, Inc.), similarly using the protocol in the synthesis of 2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine. MS (ESI, +ve ion) m/z 141.2 (M+1)⁺.

The title compound was synthesized, from cis-tert-butyl 3,5-dimethylpiperazine-1-carboxylate (AK Scientific), similarly using the protocol in the synthesis of 2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine. MS (ESI, +ve ion) m/z 173.2 (M+1)⁺.

The title compounds were synthesized and used as a mixture, from cis-tert-butyl 3,5-dimethylpiperazine-1-carboxylate (AK Scientific), similarly using the protocol in the synthesis of 2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine. MS (ESI, +ve ion) m/z 157.1 and 115.3 (M+1)⁺.

The title compound was synthesized, from (S)-tert-butyl 3-methylpiperazine-1-carboxylate, similarly using the protocol in the synthesis of 2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine. MS (ESI, +ve ion) m/z 143.2 (M+1)⁺.

The title compound was synthesized, from 1,4-dioxepan-6-one (Enamine), similarly using the protocol in the synthesis of 2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine. MS (ESI, +ve ion) m/z 187.2 (M+1)⁺.

The title compound was synthesized, from (3S,5S)-tert-butyl 3,5-dimethylpiperazine-1-carboxylate (Anichem), similarly using the protocol in the synthesis of 2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine. MS (ESI, +ve ion) m/z 157.2 (M+1)⁺.

The title compound was synthesized, from piperazin-2-one (AK Scientific), similarly using the protocol in the synthesis (Step 1) of 2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine.

The title compound was synthesized, from tert-butyl piperazine-1-carboxylate, similarly using the protocol in the synthesis of 2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazine. MS (ESI, +ve ion) m/z 157.1 (M+1)⁺.

To a stirred solution of 5,6-dihydro-2h-pyran-2-one (0.228 mL, 2.65 mmol) in DCM (1.0 mL) was added under argon a solution of piperazine-1-carboxylic acid tert-butyl ester (469 mg, 2.52 mmol) in DCM (2.0 mL). The resulting mixture was stirred at room temperature for a period of 3 d before trifluoroacetic acid (2.5 mL, 33.7 mmol) was added dropwise via a syringe. The resulting mixture was stirred at room temperature for a period of 2 h. The mixture was concentrated in vacuo and the residue was dried to give impure 4-(piperazin-1-yl)tetrahydro-2H-pyran-2-one. This was used without further purification. MS (ESI, +ve ion) m/z 185.1 (M+1)⁺.

Step 1: 2-benzyl-8,8-difluorooctahydro-1H-pyrido[1,2-a]pyrazine AND 2-benzyl-8-fluoro-2,3,4,6,7,9a-hexahydro-1H-pyrido[1,2-a]pyrazine AND 2-benzyl-8-fluoro-2,3,4,6,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazine

To a stirred solution of 2-benzylhexahydro-1H-pyrido[1,2-a]pyrazin-8(2H)-one (200 mg, 0.819 mmol, AstaTech) in DCM (5.0 mL) cooled in brine-ice bath was added bis(2-methoxyethyl)aminosulfur trifluoride solution (50% in THF, 0.989 mL, 2.456 mmol) dropwise via a syringe. The resulting mixture was stirred for 2 h at −5° C. and 3 h at ambient temperature. The crude mixture was directly loaded onto a silica gel precolumn (25 g) and subjected to flash column chromatography on a 12 g ISCO gold column eluting with 0% to 10% MeOH/DCM to give 170 mg of a mixture of 2-benzyl-8,8-difluorooctahydro-1H-pyrido[1,2-a]pyrazine, 2-benzyl-8-fluoro-2,3,4,6,7,9a-hexahydro-1H-pyrido[1,2-a]pyrazine, and 2-benzyl-8-fluoro-2,3,4,6,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazine. The mixture was directly used in the next step. MS (ESI, +ve ion) m/z 267.2 and 247.2 (M+1)⁺.

Step 2: 8,8-difluorooctahydro-1H-pyrido[1,2-a]pyrazine AND 8-fluorooctahydro-1H-pyrido[1,2-a]pyrazine

A mixture of 2-benzyl-8,8-difluorooctahydro-1H-pyrido[1,2-a]pyrazine, 2-benzyl-8-fluoro-2,3,4,6,7,9a-hexahydro-1H-pyrido[1,2-a]pyrazine and 2-benzyl-8-fluoro-2,3,4,6,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazine (250 mg, 0.939 mmol) and palladium (5 wt % dry basis on activated carbon, wet, degussa type, spatula tip) in EtOH (25 mL) and concentrated hydrochloric acid (5 mL) was hydrogenated with hydrogen gas at 40-45 psi for a period of 22 h. The reaction was quenched with water (5 mL) and the mixture was filtered through a layer of celite covered with sand. The filtrate was concentrated in vacuo to give 8,8-difluorooctahydro-1H-pyrido[1,2-a]pyrazine AND 8-fluorooctahydro-1H-pyrido[1,2-a]pyrazine as a colorless film which was used without further purification. MS (ESI, +ve ion) m/z 177.2 and 159.2 (M+1)⁺.

Step 1: tert-butyl 4-(3-acetyl-4-hydroxyphenyl)piperazine-1-carboxylate

To a stirred ice-cooled mixture of 5′-bromo-2′-hydroxyacetophenone (2.000 g, 9.30 mmol, Oakwood), 1-boc-piperazine (2.77 g, 14.88 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.426 g, 0.465 mmol), and 2-(dicyclohexylphosphino)-2′-(n,n-dimethylamino)biphenyl (0.183 g, 0.465 mmol) in THF (20 mL) was added dropwise lithium bis(trimethylsilyl)amide (1.0 M in THF, 32.6 mL, 32.6 mmol). The resulting mixture was stirred at ambient temperature for 10 min before it was placed in an oil bath which was at room temperature. The oil bath was then heated to 70° C. and the reaction mixture was stirred at this temperature for 1.5 h. The mixture was cooled in an ice bath before carefully quenched with ice-cold saturated ammonium chloride aqueous solution. The resulting mixture was poured into a mixture of 1 N aqueous HCl and saturated ammonium chloride aqueous solutions and extracted with 10% MeOH/DCM (2×). The combined organics were washed with saturated ammonium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was dissolved in DCM and loaded onto silica gel precolumn and subjected to flash column chromatography on a 40 g ISCO gold column eluting with 0% to 4% MeOH/DCM to give 1.84 g tert-butyl 4-(3-acetyl-4-hydroxyphenyl)piperazine-1-carboxylate that was directly used in the next step. MS (ESI, +ve ion) m/z 321.2 (M+1)⁺.

Step 2: tert-butyl 4-(3-acetyl-4-(trifluoromethylsulfonyloxy)phenyl)piperazine-1-carboxylate

To a stirred solution of impure tert-butyl 4-(3-acetyl-4-hydroxyphenyl)piperazine-1-carboxylate (1.30 g, 4.06 mmol) and triethylamine (2.258 mL, 16.23 mmol) in DCM (15 mL) was added N-phenyl bis-trifluoromethane sulfonimide (2.90 g, 8.12 mmol) in one portion as a solid. The resulting mixture was stirred at ambient temperature for 2.5 d. The crude mixture was directly loaded onto a silica gel precolumn (25 g) and subjected to flash column chromatography on a 40 g ISCO gold column eluting with 10% to 40% EtOAc/Hexanes to give tert-butyl 4-(3-acetyl-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)piperazine-1-carboxylate (1.4 g, 3.09 mmol, 76% yield). MS (ESI, +ve ion) m/z 475.1 (M+1)⁺.

Step 3: tert-butyl 4-(3-acetyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate

A 25-mL single-necked round bottom flash previously charged with tert-butyl 4-(3-acetyl-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)piperazine-1-carboxylate (1.17 g, 2.59 mmol), bis(pinacolato)diboron (1.642 g, 6.46 mmol), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.189 g, 0.259 mmol), and potassium acetate (0.888 g, 9.05 mmol) was subjected to 3 cycles of evacuation and back-filling with nitrogen before 1,4-dioxane (12 mL) was added. The resulting mixture under argon was placed in an oil bath and heated to 50° C. and stirred under argon at this temperature for a period of 20 h. The temperature was lowered to 45° C. and the mixture was stirred overnight at this temperature. The crude reaction mixture was run through a silica gel plug. The filtrate was concentrated in vacuo and the residue was dissolved in DCM and loaded onto silica gel precolumn (25 g) and subjected to flash column chromatography on a 24 g ISCO gold column eluting with 0% to 40% EtOAc/hexanes to give tert-butyl 4-(3-acetyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (380 mg, 0.883 mmol, 34.1% yield) as a solid. MS (ESI, +ve ion) m/z 431.3 (M+1)⁺.

Step 4: 1-(5-(piperazin-1-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanone

tert-Butyl 4-(3-acetyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate in DCM was treated with TFA for the removal the Boc group. 1-(5-(piperazin-1-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanone was isolated after concentration and used without further purification. MS (ESI, +ve ion) m/z 331.2 (M+1)+.

(2S)—N,N-BIS(4-METHOXYBENZYL)-2-METHYLPENT-4-ENE-1-SULFONAMIDE AND (2R)-N,N-BIS(4-METHOXYBENZYL)-2-METHYL-4-PENTENE-1-SULFONAMIDE

The title compound was prepared from Intermediate EE12 and pent-4-en-2-yl 4-methylbenzenesulfonate following a similar procedure described below.

(2R,3R)-N,N-BIS (4-METHOXYBENZYL)-3-METHYLHEX-5-ENE-2-SULFONAMIDE AND (2S,3R)-N,N-BIS(4-METHOXYBENZYL)-3-METHYLHEX-5-ENE-2-SULFONAMIDE

N,N-bis(4-methoxybenzyl)ethanesulfonamide (Intermediate EE13; 1030 mg, 2.95 mmol) was azeotroped in toluene under vacuum for 2 h. Under argon, THF was added and the solution was cooled to −78° C. N-butyllithium solution (2.5 M in hexane, 1.533 mL, 3.83 mmol) was then added and the mixture was stirred at −78° C. for 60 min. (S)-pent-4-en-2-yl 4-methylbenzenesulfonate (prepared according to the procedure by Sigman, M. S. et al., J. Am. Chem. Soc., 2012, 134(28), 11408-11411; 1417 mg, 5.90 mmol) was added as a solution in 3 mL. THF was then added. After 5 min the mixture was allowed to warm to ambient temperature and stirred overnight under argon. The mixture was quenched with satd NH₄Cl and extracted with EtOAc, dried over MgSO₄, and concentrated. The crude material was injected into a SiO₂ gel cartridge and purified by chromatography through a 40 g ISCO column, eluting with 5% to 10% to 20% to 40% EtOAc in hexane, to provide a 2.3:1 mixture of the title compounds (420 mg, 1.00 mmol, 34.1% yield).

Intermediate AA11A (S)-6′-CHLORO-5-(((1R,2R)-2-((S)-1-HYDROXYALLYL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO [BENZO [B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLIC ACID

STEP 1: (R)-6-CHLORO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,2′-OXIRANE] AND (R)-6-CHLORO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,2′-OXIRANE]

A 2 L 4-necked-RBF was charged with 6-chloro-3,4-dihydro-1(2H)-naphthalenone (123 g, 681 mmol), trimethylsulfonium iodide (143 g, 701 mmol), and DMSO (1100 mL). KOH (76 g, 1362 mmol) (pellets) was added. The suspension was stirred at ambient temperature for 2 days, after which time crude ¹H NMR showed no remaining starting material. The solution was poured into 800 g of crushed ice, rinsed with MTBE (200 mL), and an additional portion of MTBE (700 mL) was added. The resulting mixture was stirred for 5 min and after partition, the bottom aqueous layer was extracted with MTBE twice (500 mL, 300 mL), and combined with the main MTBE extract. The combined organic stream was washed with brine (2×600 mL) and 330 g of Al₂O₃ (neutral) was added. The resulting suspension was stirred for 5 min at 22° C., filtered, and washed with MTBE (400 mL). The filtrate was concentrated to give the product as a red viscous oil (125 g, 94%).

STEP 2: (S)-6-CHLORO-1,2,3,4-TETRAHYDRONAPHTHALENE-1-CARBALDEHYDE AND (R)-6-CHLORO-1,2,3,4-TETRAHYDRONAPHTHALENE-1-CARBALDEHYDE

A 3 L 3-necked-RBF was charged with racemic 6-chloro-3,4-dihydro-2H-spiro[naphthalene-1,2′-oxirane] (160 g, 822 mmol) and THF (1760 mL). After the batch was cooled to −8° C. with a dry ice/IPA bath, boron trifluoride diethyl etherate (5.07 mL, 41.1 mmol) was added over 3 min. An exotherm raised the batch temp to 10° C. instantly. The batch was stirred at −5 to 0° C. for 5 min, and LC/MS analysis of a sample (quenched into cold NaHCO₃ solution) showed complete conversion. The reaction was quenched by the addition of sat. NaHCO₃ (300 mL) at −5° C. followed by MTBE (400 mL) and the mixture was transferred to a separatory funnel and rinsed with MTBE (240 mL). After partition, the aqueous layer was discarded along with some white solid (likely boric acid or borax). The organic layer was washed with brine (350 mL) and concentrated under reduced pressure to give a red oil. The crude material was used directly in Step 4.

STEP 3: (6-CHLORO-1,2,3,4-TETRAHYDRONAPHTHALENE-1,1-DIYL)DIMETHANOL

Racemic 6-chloro-1,2,3,4-tetrahydro-1-naphthalenecarbaldehyde was charged onto a 3 L 3-necked-RBF and rinsed with diethylene glycol (1000 mL). Formaldehyde (37% solution in H₂O; 652 mL, 8757 mmol) was added and the resulting biphasic emulsion was cooled to 5° C. with a dry ice/IPA bath. KOH (45% aqueous solution, 652 mL, 11.9 mol) was added over ˜30 min, maintaining the temperature below 20° C. After complete addition, the batch (20° C.) was slowly heated to 45° C. (Caution: exothermic reaction) and aged for 1 h. HPLC showed complete conversion. Some viscous insoluble tar was formed, which was removed prior to aqueous workup. To the batch was added brine (500 mL) and the mixture was extracted with DCM until the product content in the aqueous phase was less than 5%. The combined DCM extract was concentrated to 750 mL as a red oil, washed with H₂O (500 mL), and the product began to crystallize out. Upon separation, the clear top aqueous layer was discarded and the bottom layer was stirred in ice/H₂O bath for 30 min, filtered, and washed with DCM (˜100 mL) and H₂O (100 mL). The product was dried under dry air/vacuum to give a first crop (113 g, 498 mmol, 57% yield). The DCM layer from the resulting mother liquor was separated and concentrated to 200-300 g (KF=0.5%), seeded, and stirred in ice/H₂O bath for 30 min. The product was filtered, washed with DCM (50 mL), and dried in dry air/vacuum to give a second crop (14.3 g, 63.1 mmol, 7% yield) for a combined total yield of 6-chloro-1,2,3,4-tetrahydronaphthalene-1,1-diyl)dimethanol of 127 g (64%).

STEP 4: (S)-(6-CHLORO-1-(HYDROXYMETHYL)-1,2,3,4-TETRAHYDRONAPHTHALEN-1-YL)METHYL 4-BROMOBENZOATE

To a solution of 2,6-bis((R)-5,5-dibutyl-4-phenyl-4,5-dihydrooxazol-2-yl)pyridine (R,R-Kang Catalyst) (1.57 g, 2.64 mmol) in dry DCM (450 mL), copper(II) chloride (0.355 g, 2.64 mmol) was added and the resulting green colored solution was stirred at rt for 1 h. This solution was added via cannula to a solution of (6-chloro-1,2,3,4-tetrahydronaphthalene-1,1-diyl)dimethanol (30 g, 132.73 mmol) in dry DCM (800 mL). The resulting mixture was cooled to −78° C. and a light green colored precipitation was observed. A solution of 4-bromobenzoyl chloride (34.77 g, 158.79 mmol) in DCM (500 mL) was then slowly added, followed by the dropwise addition of N-ethyl-N-isopropylpropan-2-amine (20 g, 154 mmol). The resulting reaction mixture was stirred at −78° C. for 3 h, then it was quenched with pH 3 phosphate buffer (1 L) and warmed to ambient temperature with vigorous stirring. The mixture was then diluted with DCM (2 L) and the layers were separated. The organic phase was washed with pH 3 buffer (1 L), sat. NaHCO₃ (1 L), and brine (2 L) then it was dried over Na₂SO₄, filtered, and concentrated. The crude material was purified by column chromatography over SiO₂ gel (100-200 mesh, 80% DCM in hexane) to afford pure (S)-(6-chloro-1-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl 4-bromobenzoate (45 g, 84%; e.r=91.4:8.6). ChiralCel® OD-H (250 mm×4.6 mm); Mobile Phase: n-Hexane:IPA: 90:10; Run Time: 20 min; flow rate: 1 mL/min; sample preparation: IPA. Retention time (major peak)—9.32 min; Retention time (minor peak)-11.46 min).

STEP 5: (R)-(6-CHLORO-1-FORMYL-1,2,3,4-TETRAHYDRONAPHTHALEN-1-YL)METHYL 4-BROMOBENZOATE

To a stirred solution of (S)-(6-chloro-1-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl 4-bromobenzoate (100 g, 244.5 mmol) in DCM (2.5 L), Dess-Martin periodinane (121.4 g, 293.3 mmol) was added at 10° C. The cooling bath was removed after addition and the reaction mixture was stirred for 30 min at ambient temperature. H₂O (9 mL) was then added and the resulting biphasic mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. and quenched with 2 L of a 1:1 mixture of 10% Na₂S₂O₃/sat. NaHCO₃ solution. The reaction mixture was stirred further at ambient temperature for 10 min, then the layers were separated and the aqueous layer was extracted with EtOAc (2×1.5 L). The combined organic layer was washed with 1 L of 10% Na₂S₂O₃/sat. NaHCO₃ solution and 1 L of brine, then it was dried over Na₂SO₄, filtered, and concentrated. Purification of the residue by column chromatography over SiO₂ gel (100-200 mesh, 5% EtOAc/hexane) provided (R)-(6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl 4-bromobenzoate (80 g, 81%).

The enantiomeric purity of the title compound could be improved by the following procedure: (R)-(6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl 4-bromobenzoate (190 g) was added in toluene (950 mL) and heated to 50° C. to complete dissolution. The homogeneous solution was cooled to ambient temperature and seeded with racemic compound. The solution was cooled to −25° C. and aged overnight. The mother liquor was then decanted and concentrated to afford 160 g of enantiomerically enriched (R)-(6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl 4-bromobenzoate (94% ee as determined by chiral HPLC). Chiral HPLC conditions: Column: ChiralCel® OD-H (250 mm×4.6 mm); Mobile Phase: n-Hexane:IPA: 90:10. Run Time: 20 min. Flow rate: 1 mL/min. Sample preparation: ethanol. Retention time (major peak): 8.488 min (96.97%); Retention time (minor peak): 9.592 min (3.03%).

STEP 6: (R)-(6-CHLORO-1-(DIMETHOXYMETHYL)-1,2,3,4-TETRAHYDRONAPHTHALEN-1-YL)METHANOL

To a solution of (R)-(6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl 4-bromobenzoate (75 g, 183.8 mmol) in anhydrous MeOH (1 L), p-TsOH (1 g, 9.2 mmol) and trimethyl orthoformate (58.4 mL, 551 mmol) were added and the reaction mixture was refluxed until the starting material was completely consumed (˜4 h). The reaction mass was concentrated to 50% volume and diluted with THF (1 L) and 1N NaOH (1 L, 1 mol). The resulting reaction mixture was stirred at 40° C. overnight and then concentrated under reduced pressure. The residue was diluted with EtOAc (1.5 L). The aqueous layer was separated and extracted with EtOAc (2×500 mL) and the combined organic layers were washed with 1N NaOH (1 L) and brine (1 L), dried over Na₂SO₄ and concentrated under reduced pressure. The crude material was purified by column chromatography over 100-200 mesh size SiO₂ gel (10% EtOAc/hexane) to give pure (R)-(6-chloro-1-(dimethoxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methanol as a light brown thick oil (44 g, 89%).

STEP 7: TERT-BUTYL-4-FLUORO-3-NITROBENZOATE

To a solution of 4-fluoro-3-nitrobenzoic acid (100 g, 540.2 mmol) in t-butanol (2.5 L), DMAP (13.18 g, 108.04 mmol) and di tert-butyl dicarbonate (248 mL, 1080.4 mmol) were added and the reaction mixture was heated at 40° C. overnight. Upon completion, the reaction mixture was diluted with H₂O and the aqueous phase was extracted with EtOAc (3×1.5 L). The combined organic layer was washed further with H₂O (1×1 L), brine (1×1 L), and dried over Na₂SO₄. The solvent was removed under reduced pressure and the crude material thus obtained was purified by column chromatography (100-200 mesh size SiO₂ gel, eluting with a gradient of 100% hexane to 5% EtOAc in hexane) affording pure tert-butyl-4-fluoro-3-nitrobenzoate (70 g, 54%) as light yellow solid.

STEP 8: (R)-TERT-BUTYL 4-((6-CHLORO-1-(DIMETHOXYMETHYL)-1,2,3,4-TETRAHYDRONAPHTHALEN-1-YL)METHOXY)-3-NITROBENZOATE

A solution of (R)-(6-chloro-1-(dimethoxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methanol (70 g, 259.2 mmol) in dry THF (3.5 L) was cooled to 0° C. and LiHMDS (1 M in THF; 363 mL, 363 mmol) was added dropwise. After 5 min, a solution of tert-butyl 4-fluoro-3-nitrobenzoate (74.9 g, 311 mmol) in THF (500 mL) was added dropwise via dropping funnel and the resulting mixture was warmed to ambient temperature. Upon completion (˜1 h), the mixture was cooled to 0° C., quenched with sat. NH₄Cl solution (1 L) and extracted with EtOAc (3×1 L). The combined organic layers were washed with NH₄Cl (1 L) and brine (1 L), dried over Na₂SO₄ and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using 100-200 mesh size SiO₂ gel (5% EtOAc/hexane) to afford (R)-tert-butyl 4-((6-chloro-1-(dimethoxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-nitrobenzoate as yellow thick oil (110 g, 87% yield).

STEP 9A: (R)-4-((6-CHLORO-1-FORMYL-1,2,3,4-TETRAHYDRONAPHTHALEN-1-YL)METHOXY)-3-NITROBENZOIC ACID

To a solution of (R)-tert-butyl 4-((6-chloro-1-(dimethoxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-nitrobenzoate (35 g, 71.25 mmol) in MeCN (1 L), erbium triflate (4.3 g, 7.1 mmol) and H₂O (13 mL) were added. The resulting mixture was heated to 80° C. overnight. The solvent was then removed under reduced pressure and the residue was dissolved in Et₂O (1.5 L) and washed with 1N HCl (500 mL) and brine (500 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated to afford (R)-4-((6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-nitrobenzoic acid (30 g), which was used without further purification.

Alternatively, (R)-4-((6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-nitrobenzoic acid may be prepared from (6-chloro-1,2,3,4-tetrahydronaphthalene-1,1-diyl)dimethanol (Step 4) as follows:

A 250 mL 3-necked-RBF was charged with copper (II) chloride (0.095 g, 0.02 eq), 2,6-bis((R)-5,5-dibutyl-4-phenyl-4,5-dihydrooxazol-2-yl)pyridine (0.42 g, 0.02 eq) and THF (28.5 g, 4V). After inertion with N₂, the batch was stirred at 20° C. for 0.5 h. To the homogenous green solution was added (6-chloro-1,2,3,4-tetrahydronaphthalene-1,1-diyl)dimethanol (8.0 g, 1.00 eq) followed by THF (14.2 g, 2V) and 4-methylmorpholine (3.75 g, 1.05 eq). The reaction mixture was cooled to −20° C., and a solution of 1-napthoyl chloride (7.06 g, 1.05 eq) in THF (21.3 g, 3 V) was added to the batch over 0.5 h maintaining the temperature below −15° C. After aging at −20° C. for 20 h, an aliquot of the reaction slurry was sampled and assayed by HPLC. The slurry was directly filtered through a glass-fritted funnel while maintaining the temperature at −20° C. The filter cake was washed with two portions of cold (<−10° C.) THF (2×14.2 g, 2V) rinsed through the reaction vessel. The filter cake (4-methylmorpholine*HCl) was transferred to a labeled container. The mother liquor and washes were concentrated to a minimum volume and distillative solvent swap by charging toluene until the batch volume is 6V and toluene/THF ratio is >98:2 (v/v) as measured by QNMR. To the batch at 20° C. was added heptane (11 g, 2V) and the slurry was heated to 85° C. (dissolution observed). The solution was cooled to 75° C. and charged with seed (0.27 g, 0.02 eq). The slurry was cooled to 20° C. over 3 h and aged for >1 h. The batch was filtered through a glass-fritted filter and the cake was washed with toluene/heptane (3:1 v/v) (11 g, 2V) then toluene/heptane (1:1 v/v) (11 g, 2V). The cake was dried under N₂ for 12 h at ambient temperature and the cake was assayed dry by QNMR (<1 wt % toluene and heptane). The product was obtained as an off-white solid (8.75 g, 63% after wt adjustment).

A 60 L jacketed reactor vented with a bleach scrubber was charged with (S)-(6-chloro-1-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methyl 1-naphthoate (2.693 Kg, 88.6 wt %, 6.3 mol) followed by DCM (17.9 Kg, 5 vol) and EtNiPr₂ (2.84 Kg, 3.5 eq). After N₂ inertion, the batch was agitated and cooled to 0° C. To the alcohol slurry mixture in the reactor was added a solution of freshly prepared sulfur trioxide pyridine (2.10 Kg, 2.5 eq of sulfur trioxide pyridine in 7.43 Kg, 3 vol. DMSO) over 30 min while maintaining the batch temperature below 15° C. After addition, HPLC assay showed >99% conversion. The batch was quenched by the addition of H₂O (14 L, 5 vol) over ˜20 min. maintaining the batch temperature below 15° C. and then toluene (16.8 L, 6 vol) was added. After partition, the organic layer was treated with H₂O (14 L, 5 vol) and toluene (16.8 L, 6 vol). The top organic layer was washed with 2 N HCl twice (14 L each, 5 vol) and brine (14 L, 5 vol). The organic layer was drained to a clean container, assayed by HPLC and then transferred back to the clean 60 L reactor through an inline filter. The batch was concentrated to a minimal volume and solvent switched to MeOH until the batch volume was 28 L (10 vol) and MeOH/toluene ratio was 3:1 (v/v) as measured by QNMR. The batch was then transferred to a 30 L jacketed reactor through an inline filter. After adjustment of the batch temperature to 30° C., the batch was seeded with the aldehyde (51 g, 0.02 eq) as a slurry in MeOH (400 mL). After the slurry was aged for 30 min at 30° C., the batch was solvent switched by distillation with MeOH until the batch volume is 11 L (4 vol) and MeOH/toluene ratio is ≥99:1 (v/v). The batch was then cooled to 5° C. and MeOH/H₂O mixture (3.70 Kg MeOH+1.34 Kg H₂O) was added over 1.5 h to bring the total solvent volume to approximately 5.5 vol and final MeOH/H₂O to 90/10 (v/v). The batch was heated to 65° C. over 30 min, and cooled to 20° C. over 2 h and aged for ˜2 h. The batch was filtered through an Aurora® filter fitted with ≤25 μm filter cloth. The cake was washed with MeOH/H₂O (10:1) (1×2 vol), then MeOH/H₂O (2:1) (1×2 vol). The cake was dried under N₂ at ambient temperature for ≥4 h until dry to give the product as an off-white solid (1.99 Kg, 72% after wt % adjustment).

A 3-necked 250 mL RBF was charged with (R)-(6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl 1-naphthoate (10 g, 94.4 wt %, 95.3% LCAP, >99% ee), methanol (100 mL), trimethyl orthoformate (7 mL), and TsOH.H₂O (0.24 g). The RBF was inerted with N₂, and agitation was initiated. The batch was heated to 60° C. and aged for 2 h. HPLC assay showed ≥98% conversion.

The batch was concentrated under vacuum (˜150-190 torr, external temp ˜40° C.) to minimal volume using a rotoevaporator. The batch was turned over to THF by charging THF three times (50 mL each time) and distilling under vacuum (˜165 torr, external temp ˜40° C.). After each of the first two THF charges, the batch was concentrated down to a minimal volume, and after the last THF charge and distillation QNMR analysis of a sample showed the target ratio of >20/1 THF/MeOH (v/v). LiOH.H₂O (10.46 g, 10 eq) and H₂O (50 mL) were charged to the 3-necked 250 mL RBF. The reaction mixture was heated to 65° C. and aged for 18 h. HPLC assay showed >99% conversion. The batch was cooled to 20° C. and transferred to a 500-mL separatory funnel. MTBE (106 mL) was charged to the separatory funnel and the funnel was shaken well. After settling for 5 min, the bottom aqueous layer was drained. The top organic layer was washed with 20% K₂CO₃ twice (32 mL and 11 mL). The batch was transferred to a 250 mL RBF. Assay by HPLC showed <2% naphthanoic acid by-product. The batch was concentrated to a minimal volume at reduced pressure on the rotoevaporator (300 mbar, external temp ˜40° C.). The batch was turned over to THF using a rotoevaporator (˜250 mbar, external temp ˜40° C.) by adding and distilling THF (˜50 mL, ˜50 mL). After each THF charge, the batch was distilled down to a minimal volume. THF (50 mL) was charged to the 250 mL RBF. KF of a sample showed 0% H₂O (≤0.1% acceptable). The batch was polish filtered (60 mL medium-frit funnel) into a clean and dry 250 mL 3-necked-RBF using THF (50 mL) for rinsing and volume adjusting. To the batch was added 4-fluoro-3-nitrobenzoic acid (4.61 g, 1.0 eq), the mixture was cooled to −20° C., and 20% potassium tert-butoxide THF solution (40 mL) was added over 1.5 h, maintaining the batch temperature at −20±10° C. (exothermic). After complete addition, the batch was aged at −20° C. and an aliquot assayed by HPLC after 1.5 h showed 98% conversion. To the batch in the flask was added sat. NH₄Cl solution (10 mL), maintaining the temperature at −20±10° C., followed by addition of H₂O (20 mL) and MeTHF (34 mL) at −20±20° C. The mixture was warmed to 20° C. and agitated for 13 h. The batch was transferred to a separatory funnel, allowed to settle for ˜5 min, and the bottom aqueous layer was removed keeping the rag with the organic stream. The top organic stream was washed with sat. NH₄Cl solution (10 mL) and H₂O (20 mL) at 20° C. After ˜5 min of settling, the aqueous layer was separated. To the total crude organic stream (KF=14%) was added MSA (4 mL) in a 250 mL 3-necked-RBF. The batch was heated to reflux (65° C.) for 25 h and LC assay showed full conversion (≥97%).

The batch was cooled to <20° C. and K₃PO₄.H₂O (4.5 g) and H₂O (7 mL) were added. The batch was transferred to a separatory funnel and the bottom aqueous layer was drained to give the aldehyde product crude solution. The combined organic crude stream was concentrated to minimum volume using a rotary evaporator. To the batch in a 500 mL RBF was charged AcOH (˜50 mL, ˜50 mL) and distilled using a rotary evaporator at reduced pressure (30 mbar, external temp ˜40° C.). The THF level was measured by QNMR and none was observed. The mixture was transferred to a 250 mL 3-necked RBF and AcOH was added to adjust the total volume to ˜40 mL, when crystallization occurred. To the batch was added H₂O (12 mL) over ˜1 h. After aging for >1 h, LC assay of supernatant concentration was 9 mg/mL. If concentration is >10 mg/mL then a small portion of H₂O (0.2 vol) can be added; after checking by LC, repeat if necessary. The batch was filtered, washed with 20% H₂O/AcOH (23 mL) and dried under N₂/vacuum for 3.25 h to give the title compound (8.22 g) as an off-white solid (82% yield corrected for purity).

STEP 9B: (R)-TERT BUTYL 4-((6-CHLORO-1-FORMYL-1,2,3,4-TETRAHYDRONAPHTHALEN-1-YL)METHOXY)-3-NITROBENZOATE

To a solution of (R)-tert-butyl 4-((6-chloro-1-(dimethoxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-nitrobenzoate (1 g, 2.033 mmol) in anhydrous acetone (41 mL) was added Amberlyst®-15 (1 g, 2.033 mmol; prewashed with 2×10 mL dry acetone). The mixture was heated to 50° C. for 3.5 h, then filtered and rinsed with DCM. The filtrate was concentrated and dried under high vacuum overnight (it turned a dark red color). LC/MS and NMR analysis suggested ˜10% of corresponding carboxylic acid was present as well as 0.5 eq mesityl oxide. The mixture was advanced to Step 11 without further purification.

STEP 10: (S)-6′-CHLORO-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO [BENZO [B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLIC ACID

A solution of crude (R)-4-((6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-nitrobenzoic acid (30 g, 77.10 mmol) in AcOH (1 L) was heated to 70° C. and iron powder (28 g, 500 mmol) was added. The resulting mixture was heated for ˜4 h at 70° C. AcOH was then removed under reduced pressure and the residue was dissolved in DCE (1 L). Sodium triacetoxy borohydride (46.5 g, 740 mmol) was added portion-wise and the reaction mixture was stirred at ambient temperature for 1 h. The reaction was then quenched with H₂O followed by 10% aqueous citric acid (500 mL). The aqueous phase was extracted with DCM (2×1 L) and the combined organic layer was washed with brine (500 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography using 100-200 mesh size SiO₂ gel (40% EtOAc/hexane) to afford pure (S)-6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid as white solid (24 g, 99% after two steps).

Alternatively, (S)-6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid with ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid (1:1) may be prepared as follows:

A pressure reactor was charged with (R)-4-((6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-nitrobenzoic acid (20 g, 94 wt %), 5% Pt/S/C wet (2.2 g), THF (400 mL) and titanium isopropoxide (0.5 mL). The reactor was sealed, purged with inert gas (3 cycles, at least once with stirring), and then purged with H₂ (1 cycle). The reactor was pressurized with H₂ to 70 psig, stirring (950 rpm) was initiated, and the temperature was increased to 90° C. maintaining the H₂ pressure in the reactor (70 psig at 22-30° C., 80 psig at 50-60° C. and 90 psig at 88-91° C.). After 16 h, the reactor was cooled to ambient temperature and purged with inert gas (3 cycles). HPLC analysis of the reaction confirmed >98% conversion.

The reaction mixture was filtered through a Celite® pad (2 inch) using additional THF for rinses, and the filtrate was concentrated under reduced pressure at 40° C. To the residue was added IPA (60 mL) and 2-4% aqueous MeOH (10 mL). The mixture was stirred for 10 min and then it was filtered through a Celite® pad (2 inch). MeOH was evaporated under reduced pressure at 40° C. and to the concentrated IPA solution cooled to ambient temperature was added a solution of +CSA (56.0 g) in IPA (200 mL) dropwise over 2 h. After 10% of the CSA solution has been added, the mixture was seeded with crystals of the title compound (10-15 mg) followed by the addition of the remaining CSA solution. After stirring at ambient temperature overnight, the mixture was filtered, and the filter cake was washed with 100 mL of IPA and dried under vacuum/N₂ at ambient temperature. The product is isolated as a white solid: (S)-6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid with ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid (1:1) (85-88% yield, >99.5% ee).

STEP 11A: (S)-METHYL 6′-CHLORO-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO [BENZO [B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

To a solution of (S)-6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid (130 g, 379 mmol) in methanol (6 L) was added Amberlyst®-15 (130 g, pre-washed with anhydrous methanol) and heated to reflux for 10 h. Amberlyst® was then removed by filtration and rinsed with methanol (3×300 mL). The combined filtrate was concentrated and the residue was purified by column chromatography to give pure (S)-methyl 6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate as a white solid (105 g, 77%). Chiral HPLC conditions: Column: ChiralCel® OD-H (250 mm×4.6 mm, 5 □m); Mobile Phase: n-Hexane:EtOH: 95:05. Run Time: 25 min. Flow rate: 1 mL/min. Retention time (minor peak): 10.162 min (1.98%); Retention time (major peak): 12.292 min (98.02%).

STEP 11B: (S)-TERTBUTYL 6′-CHLORO-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO [BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

To a solution of (R)-tert-butyl 4-((6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-nitrobenzoate (0.9 g, 2.018 mmol) in AcOH (20.22 mL, 353 mmol) at 70° C. was added iron (0.676 g, 12.11 mmol). The mixture was stirred vigorously for 4 h, then concentrated, and the residue was diluted with 20 mL 1,2-DCE. Sodium triacetoxyhydroborate (1.711 g, 8.07 mmol) was added and the mixture was stirred at ambient temperature for 20 min.

Upon quenching by addition of 20 mL H₂O, a thick slurry was formed. 20 mL 10% citric acid solution was added and the mixture became lighter in color. The layers were separated and the aqueous layer was extracted with 2×20 mL DCM. The combined organics were washed with 10 mL 10% citric acid and 10 mL brine, dried over MgSO₄, filtered, and concentrated. The residue was deposited on 3 g SiO₂ gel and purified using 5-10% EtOAc in hexane to give (S)-tert-butyl 6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (557 mg, 1.393 mmol, 69.0% yield). Further elution with 30% EtOAc in Hex provided (S)-6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid (132 mg, 0.384 mmol, 19.02% yield).

STEP 12: (1R,2S)-1,2-CYCLOBUTANEDIYLDIMETHANOL

To a rapidly stirred solution of LAH (1.0 M solution in THF, 1000 mL, 1000 mmol) at ambient temperature in a 3000 mL 3-necked RBF under a stream of argon, solid (1R,5S)-3-oxabicyclo[3.2.0]heptane-2,4-dione (40 g, 317 mmol) was gradually added over 2 h, maintaining the internal temperature of the reaction mixture below 50° C. The reaction was stirred overnight at ambient temperature under argon. After 16 h, the reaction mixture was cooled by an ice bath to 10° C., and, under a fast stream of argon, a solution of 36 mL H₂O was added drop wise by addition funnel at a rate that maintained the temperature between 12-15° C., approximately 1 mL/min, with vigorous stirring (500 rpm). The mixture was then vigorously stirred (500 rpm) in the ice-bath for 1 h, then removed from the bath and stirred to rt for 1 h before cooling again with an ice bath to 5-10° C. To the mixture was added 36 mL of a 15% NaOH aqueous solution over a period of 45 min, maintaining the temperature between 10-20° C. To the mixture was added 108 mL H₂O drop wise by addition funnel, maintaining the temperature between 10-20° C., over ˜1 h. Upon completed addition of the H₂O, the flask was removed from the ice bath, equilibrated to rt and left to stir vigorously under argon overnight. After stirring for 16 h, the mixture was filtered and the filtrate concentrated under reduced pressure to afford a colorless, slightly opaque oil. The oil was taken up in Et₂O and stirred over anhydrous MgSO₄ and filtered through a pad of Celite®. The filtrate concentrated under reduced pressure to afford 32.8 g of a colorless oil, which was used in the next step without further purification (89% yield).

STEP 13: CIS-CYCLOBUTANE-1,2-DIYLBIS(METHYLENE) DIACETATE

Ac₂O (2.59 mL; 3.0 eq) was added to the CIS-1,2-cyclobutanediyldimethanol (1.06 g, 9.15 mmol) and the resulting solution was heated to 50° C. After stirring overnight, the mixture was assayed by GC and showed complete conversion. The mixture was then diluted with 15 mL of heptane and concentrated under vacuum to give a clear oil. The oil was dissolved in 15 mL heptane and concentrated back down to an oil (azeotropic removal of Ac₂O) to give the title compound as an oil (1.827 g, 88% yield, 88.3% purity by QNMR using benzyl benzoate as an internal standard).

STEP 14: ((1R,2S)-2-(HYDROXYMETHYL)CYCLOBUTYL)METHYL ACETATE

A 12 L 3-neck-RBF equipped with mechanical stirrer was charged with a 1M sodium citrate solution (prepared by mixing sodium citrate tribasic dihydrate; 682 g, 2320 mmol) and H₂O to reach total volume ˜2.3 L) and 3.48 L H₂O (˜25° C.). The mixture was cooled using an ice/H₂O bath to ˜20.2° C. pH-8.46 (measured with pH probe). Amano Lipase from Pseudomonasfluorescens (41.8 g, 1547 mmol) was then added in one charge (pH ˜8.12) and the mixture was vigorously stirred at ambient temperature for ˜5 min. (1R,2S)-cyclobutane-1,2-diylbis(methylene) diacetate (348 g, 1547 mmol) was added in one charge and the resulting mixture was stirred vigorously at ambient temperature monitoring internal temperature and pH. After stirring the mixture overnight (˜20.9° C. and pH˜5.45) an aliquot was collected, extracted with IPAc, diluted with MeCN and analyzed by GC and the reaction was deemed complete (1.21% SM leftover, 0.17% of enantiomer, 1.8% of diol). Celite® (70 g) added to the reaction mixture and the slurry was filtered through a Celite® pad on a medium porosity glass filter (fast filtration, 15-20 min), rinsing with 2.5 L IPA. The biphasic mixture was transferred into a 12 L-extractor and stirred for 1 min. The aqueous layer was separated and extracted with IPAc (1×4 L), and the combined organic extract was concentrated in vacuo obtaining 337.28 g (99.6% ee; ˜50-60 mol % of residual IPA by ¹HNMR; QNMR: 37.63 mg+benzyl benzoate (Aldrich catalog#B6630, lot# MKBG9990V, 61.27 mg; Result: ˜65 wt %; corrected yield 89%). The crude product was used as such for the next step.

STEP 15: ((1R,2R)-2-FORMYLCYCLOBUTYL)METHYL ACETATE

A 2-L Atlas reactor was charged with ((1R,2S)-2-(hydroxymethyl)cyclobutyl)methyl acetate (126.39 g, 79.6 wt % by QNMR; 636 mmol) and 1 L of DCM and the jacket temperature was set to 20° C. Iodobenzene diacetate (225 g, 700 mmol) was added as a solid (endothermic addition: the temperature decreased to 15° C.). TEMPO (3.97 g, 25.4 mmol) was added as a solid in one portion resulting in a cloudy orange solution, which became clear over the course of 20 min. After stirring at 20° C. overnight, an aliquot was collected, diluted with MeOH, and analyzed by GC. An Additional kicker charge of iodobenzene diacetate and TEMPO can be used to push the reaction to completion if necessary. The reaction mixture was then cooled to 1.8° C. (internal temperature, ice/dry ice/H₂O bath) and DIPEA (194 mL, 1113 mol) was added drop-wise via addition funnel over 65 min keeping internal temperature <5° C. The cooling bath was removed and the mixture was allowed to warm to ambient temperature with stirring. After 48 h an aliquot was collected, diluted with methanol, and analyzed by GC showing a 12:1 ratio of trans:cis isomers. The reaction mixture was then cooled to <5° C. (ice/H₂O bath) and H₂O (230 mL) was added over ˜10 min (internal temperature reached 14° C.). The organic layer was separated, washed with H₂O (125 mL) and 1M aqueous NaH₂PO₄ (90 mL) and concentrated in vacuo to afford 273.4 g of ((1R,2R)-2-formylcyclobutyl)methyl acetate (QNMR: 68.85 mg+benzyl benzoate (Aldrich catalog# B6630, Lot#MKBG9990V, 72.36 mg). The crude product was used as such for next step.

STEP 16: ((1R,2R)-2-((R)-(1H-BENZO[D][1,2,3]TRIAZOL-1-YL)(HYDROXY)METHYL)CYCLOBUTYL)METHYL ACETATE

To a solution of crude ((1R,2R)-2-formylcyclobutyl)methyl acetate (5 g, 10.27 mmol) in 8 mL MTBE was added benzotriazole (1.296 g, 10.00 mmol) as a solid (slightly exothermic). The clear solution became increasingly cloudy and a precipitate formed. The mixture was allowed to equilibrate overnight at ambient temperature then heptane was added (6 mL). After aging for 6 h the mixture was filtered at ambient temperature and washed with 10 mL of 1:1 MTBE/heptane. The white solid was air dried on the frit under vacuum obtaining 2.48 g of ((1R,2R)-2-((R)-(1H-benzo[d][1,2,3]triazol-1-yl)(hydroxy)methyl)cyclobutyl)methyl acetate.

STEP 17: (S)-METHYL 5-(((1S,2R)-2-ACETOXYCYCLOBUTYL)METHYL)-6′-CHLORO-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO [BENZO [B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

((1R,2R)-2-Formylcyclobutyl)methyl acetate (from Step 16; 4.36 g, 27.9 mmol) was added to a solution of (S)-methyl 6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (5.0 g, 13.97 mmol) (Step 12) in DCM (78 mL) and AcOH (38.8 mL). The solution was stirred at ambient temperature for 10 min, then cooled to 0° C., and sodium cyanoborohydride (1.463 mL, 27.9 mmol) was added slowly over 1 h. The mixture was stirred at 0° C. for 10 min, then poured slowly into cold NaOH solution, and extracted with EtOAc (120 mL). The organic phase was washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was loaded to a 220 g ISCO gold column and eluted with 0% to 10% EtOAc/hexane to provide the title compound 6.0 g of the title compound as a white solid. m/z (ESI +ve ion) 498.1 (M+H)⁺.

STEP 18A: (S)-METHYL 6′-CHLORO-5-(((1R,2R)-2-(HYDROXYMETHYL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO [BENZO [B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

KOH (0.278 mL, 10.14 mmol) was added to a solution of (S)-methyl 5-(((1R,2S)-2-(acetoxymethyl)cyclobutyl)methyl)-6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (from Step 18; 1.530 g, 3.07 mmol) in MeOH (99 mL). The mixture was stirred at ambient temperature for 4 h, then neutralized with 1N HCl to pH=7, and concentrated under reduced pressure. The aqueous residue was extracted with EtOAc (400 mL) and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, and filtered through a short plug of SiO₂ gel to afford the title compound as a white solid. (1.354 g was obtained. m/z (ESI, +ve ion) 456.2 (M+H)⁺)

Alternatively, (S)-methyl 6′-chloro-5-(((1R,2R)-2-(hydroxymethyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate may be prepared as follows:

To a slurry of (S)-6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid with ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid (1:1) (Step 11) (32.22 g, 52.5 mmol) and ((1R,2R)-2-((R)-(1H-benzo[d][1,2,3]triazol-1-yl)(hydroxy)methyl)cyclobutyl)methyl acetate (Step 17) (15.89 g, 57.7 mmol) in DCM (226 mL, 7 mL/g) was added sodium triacetoxylborohydride (13.90 g, 65.6 mmol) in 4 portions over 30 min. Additional ((1R,2R)-2-((R)-(1H-benzo[d][1,2,3]triazol-1-yl)(hydroxy)methyl)cyclobutyl)methyl acetate (2.89 g, 10.50 mmol) and sodium triacetoxyborohydride (2.78 g, 13.12 mmol) were added to drive the reaction to completion (determined by HPLC assay). 80 mL of H₂O was then added and the resulting mixture was agitated for 5 min. The layers were separated, the organic phase was washed with 60 mL H₂O and 20 mL of brine, and then concentrated to an oil under reduced pressure. The residue was dissolved in 50 mL of MeOH and 40 mL of 5N NaOH were then added at ambient temperature (exothermic). Upon reaction completion (determined by HPLC assay), the reaction mixture was partitioned between 133 mL of MTBE and 35 mL of 1.5 M citric acid. The organic phase was transferred to a RBF and the solvent was exchanged to MeCN via atmospheric distillation. This solution was seeded at 62° C. (a slurry developed), was allowed to reach ambient temperature, and then aged overnight. The slurry was filtered at 20.5° C. through a coarse frit glass sinter funnel and the filter cake was washed using 60 mL of MeCN, then dried in a vacuum oven at 40° C. to constant weight. Final mass: 21.87 g (96.4 wt % by HPLC).

A 100 mL 3-necked-RBF was charged with (S)-6′-chloro-5-(((1R,2R)-2-(hydroxymethyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid (4.53 g, 1.0 eq), MeOH (45 mL, 10 vol), and then a prepared solution of SOCl₂ (11.28 mL, 1.0M in MeCN, 1.1 eq). Under an atmosphere of N₂, the batch was heated to 55° C. and stirred for 18 h (or until >99% conversion as determined by HPLC). The reaction mixture was then allowed to cool to 20° C. over 2 h. To the resulting white slurry was added Hunig's base (3.94 mL, 2.2 eq) and after aging for 0.5 h, H₂O (9.0 mL, 2 V) was added as antisolvent over 1 h. The white slurry was aged for >2 h and the batch was filtered through a glass-fritted filter and the cake was washed with MeOH/H₂O (5:1 v/v) (9.0 mL, 2V) then MeOH/H₂O (2:1 v/v) (9.0 mL, 2V). The cake was dried under N₂ with vacuum for 12 h at ambient temperature. The product was obtained as a white solid (4.36 g, 92% yield).

STEP 18B: (S)-TERTBUTYL 6′-CHLORO-5-(((1R,2R)-2-(HYDROXYMETHYL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO [BENZO [B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

The title compound was synthesized from (S)-tertbutyl 6′-chloro-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (Intermediate AA11A) following the procedures described for Intermediate AA11A, Steps 18-19A).

STEP 19A: (S)-METHYL 6′-CHLORO-5-(((1R,2R)-2-FORMYLCYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO [BENZO [B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

To a cooled (−70° C.) solution of DMSO (7.12 mL, 2.5 eq) and DCM (183 mL, 10 vol) in a 1 L 3-necked-RBF inerted with N₂ was added oxalyl chloride (26.1 mL, 1.0M in DCM, 1.3 eq) at a rate to maintain temperature below −70° C. The batch was aged below −70° C. for 30 min and then a prepared solution of (S)-methyl 6′-chloro-5-(((1R,2R)-2-(hydroxymethyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (from Step 19A; 18.3 g, 1.0 eq) in DCM (183 mL, 10 vol) was added at a rate to maintain reaction temperature <−70° C. The batch was aged for 1.5 h and then Et₃N (22.4 mL, 4.0 eq) was added at a rate to maintain batch temperature <−70° C. After aging for 1 h, the batch was allowed to warm to −20° C. and H₂O (366 mL, 20 vol) was added. The batch was agitated at 20° C. and the phases separated. The organic layer was washed with 2×1N HCl (183 mL, 10 vol) and brine (183 mL, 10 vol). The organic layer was polish filtered and concentrated in vacuo to afford (S)-methyl 6′-chloro-5-(((1R,2R)-2-formylcyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (19.91 g, 94% yield corrected for wt %) as a tan foam.

STEP 19B: (S)-TERTBUTYL 6′-CHLORO-5-(((1R,2R)-2-FORMYLCYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO [BENZO [B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

The title compound was synthesized from (S)-tertbutyl 6′-chloro-5-(((1R,2R)-2-(hydroxymethyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (Intermediate AA 11A, Step 19B) following the procedure described for Intermediate AA11A, step 20A.

STEP 20: (S)-METHYL 6′-CHLORO-5-(((1R,2R)-2-((S)-1-HYDROXYALLYL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO [BENZO [B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

An oven dried 3-necked-RBF equipped with a pressure-equalizing addition funnel, thermocouple, and magnetic stirbar was cooled to ambient temperature under a purge of argon gas. The flask was charged with (1R,2S)-2-morpholino-1-phenylpropan-1-ol (40.2 g, 182 mmol; prepared according to the literature procedure by Brubaker, J. D.; Myers, A. G. Org. Lett. 2007, 9, 3523-3525) against a positive pressure of argon. The addition funnel was charged with toluene (450 mL), which was dropped into the reactor. The solution was cooled in an ethyleneglycol-CO₂ bath (˜−12° C.) and treated with butyllithium solution (2.5 M in hexane, 72.6 mL, 182 mmol), causing a white solid to precipitate that gradually went into solution as it was stirred over 30 min. Divinylzinc solution (605 mL, 182 mmol; prepared according to Brubaker, J. D.; Myers, A. G. Org. Lett. 2007, 9, 3523-3525. The concentration of divinylzinc solution was determined by titrating against iodine (Krasovskiy, A.; Knochel, P. Synthesis 2006, 890-891; concentration was generally ˜0.25M) was added, and the solution was aged with stirring in the cold bath for 1 h; the internal temperature was −15° C. (S)-methyl 6′-chloro-5-(((1R,2R)-2-formylcyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (from Step 20A; 48.5 g, 107 mmol) (azeotroped thrice with toluene) was added as a solution in toluene (200 mL, 150 mL+2×25 mL cannula/vial rinse) via cannula, over ˜20 min. The internal temperature rose to −10° C. The mixture was stirred for 90 min while maintaining the internal reaction temperature below −5° C. The addition funnel was charged with 30% w/w aqueous citric acid (450 mL), then the reaction was quenched by adding the solution to the reaction mixture. The reactor was removed from the bath and permitted to stir at ambient temperature. The solution was transferred to a separatory funnel and the flask was rinsed with toluene and 30% aqueous citric acid (50 mL each). The layers were mixed and then separated. The organic layer was washed with H₂O (250 mL), then brine (250 mL), and finally dried with MgSO₄. The solution was filtered and concentrated to yield a yellow oil, ˜90 g after vacuum overnight, 20:1 dr. This was split into 3 batches and purified by column chromatography 10 to 20% EtOAc/hexane 1.5 kg SiO₂, to provide (S)-methyl-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (43.3 g, 84%). The aqueous layer and washings were placed in an ice/H₂O bath and basified to pH >13 by addition of 8N aqueous NaOH. This solution was then extracted with toluene (3×250 mL). The combined organic extracts were washed with H₂O (250 mL) and brine (250 mL), then dried with MgSO₄. The solution was filtered and concentrated to recover the ligand in >95% yield.

STEP 21: (S)-6′-CHLORO-5-(((1R,2R)-2-((S)-1-HYDROXYALLYL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO [BENZO [B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLIC ACID

To a solution of (S)-methyl 6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (from Step 21; 4.59 g, 9.52 mmol) in a mixture of THF (18 mL), MeOH (6.00 mL) and H₂O (6.00 mL) was added LiOH.H₂O (0.799 g, 19.05 mmol) and the reaction was stirred at 50° C. for 4 h. The reaction mixture was concentrated to ˜15 mL, cooled to 0° C. and acidified with 2N HCl to pH=3. The resulting viscous oil was diluted with 20 mL of H₂O and 50 mL of EtOAc and a clear two-layer mixture was obtained. More EtOAc (ca. 200 mL) was added and the organic layer was separated, washed with brine, dried with MgSO₄, filtered and concentrated under reduced pressure. The crude material was loaded onto a column (220 g), and purified with EtOAc in hexane using the following gradient: 0-2.5 min 0% of EtOAc, 2.5-6 min 0-20% EtOAc, 6-35 min 20-60% EtOAc, 35-40 min 70% EtOAc to give (S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro [benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid (4.22 g, 9.02 mmol, 95% yield) as a white solid.

Intermediate AA12A (S)-6′-CHLORO-5-(((1R,2R)-2-((S,E)-1-HYDROXYHEX-2-EN-1-YL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO [BENZO [B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLIC ACID

STEP 1A: (S)-METHYL 6′-CHLORO-5-(((1R,2R)-2-((S,E)-1-HYDROXYHEX-2-EN-1-YL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO [BENZO [B][1,4] OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

Under argon atmosphere, a dry 3-necked-RBF charged with dry hexane (27 mL) was cooled to 0° C. To this solution was added borane-methyl sulfide complex (3.29 mL, 34.6 mmol) and cyclohexene (7.01 mL, 69.3 mmol) and the mixture was stirred at 0° C. for 2 h. To the resulting white suspension was added 1-pentyne (3.41 mL, 34.6 mmol) and the mixture was stirred at ambient temperature for 0.5 h. The mixture was then cooled to −78° C. and diethylzinc, 1.0 M solution in hexane (32.3 mL, 32.3 mmol) was added. After addition the mixture was warmed to 0° C., stirred for 3 min then recooled to −78° C. This solution was named solution A. A separate flask was charged with a mixture of ((S)-methyl 6′-chloro-5-(((1R,2R)-2-formylcyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (Intermediate AA11A, Step 20A, 5.24 g, 11.54 mmol) and (2s)-3-exo-(morpholino) isoborneal (0.486 g, 2.032 mmol) in hexane (50.9 mL) and toluene (16.97 mL). The mixture was stirred at ambient temperature until all solid was dissolved, then cooled to 0° C. Under argon atmosphere 54 mL of solution A was added slowly via syringe during 1.6 h. After stirring for 5 min at 0° C., the mixture was quenched with sat. NH₄Cl solution (70 mL), diluted with H₂O (30 mL) and extracted with EtOAc (3×270 mL), washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was loaded to a 330 g ISCO gold column and eluted with 0% to 5% EtOAc/hexane, to provide the title compound 3.8 g as a white solid. m/z (ESI, +ve ion) 524.1 (M+H)⁺.

STEP 1B: (S)-TERTBUTYL 6′-CHLORO-5-(((1R,2R)-2-((S,E)-1-HYDROXYHEX-2-EN-1-YL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO [BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE AND (S)-TERTBUTYL 6′-CHLORO-5-(((1R,2R)-2-((R,E)-1-HYDROXYHEX-2-EN-1-YL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO [BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

The title compound was synthesized from (S)-tert-butyl 6′-chloro-5-(((1R,2R)-2-formylcyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (3.19 g, Intermediate AA11A, Step 20B) following the procedure described for Intermediate AA12A, Step 1A. The crude material was absorbed onto a plug of SiO₂ and purified on a 330 g ISCO gold column eluting with 0 to 15% EtOAc in heptanes over 45 min to provide (S)-tertbutyl 6′-chloro-5-(((1R,2R)-2-((S,E)-1-hydroxyhex-2-en-1-yl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (2.36 g). Further elution provided (S)-tert-butyl 6′-chloro-5-(((1R,2R)-2-((R,E)-1-hydroxyhex-2-en-1-yl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (0.45 g).

STEP 2: (S)-6′-CHLORO-5-(((1R,2R)-2-((S,E)-1-HYDROXYHEX-2-EN-1-YL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO [BENZO [B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLIC ACID

A mixture of (S)-methyl 6′-chloro-5-(((1R,2R)-2-((S,E)-1-hydroxyhex-2-en-1-yl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (from Intermediate AA12A, Step A; 4.6 g, 8.78 mmol) and LiOH.H₂O (3.68 g, 88 mmol) in MeOH (98 mL) and THF (98 mL) (with a few drops of H₂O) was stirred at 50° C. overnight. The solvent was removed and the residue was acidified with 1N HCl to pH 2-3. The mixture was extracted with EtOAc (80 mL×3) and the combined organic layer was washed with brine (10 mL), dried over anhydrous MgSO₄ and concentrated under reduced pressure to give (S)-6′-chloro-5-(((1R,2R)-2-((S,E)-1-hydroxyhex-2-en-1-yl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid (4.25 g, 8.34 mmol, 95% yield).

Alternatively, the title compound may be synthesized as follows:

To a solid mixture of (S)-tert-butyl 6′-chloro-5-(((1R,2R)-2-((S,E)-1-hydroxyhex-2-en-1-yl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (Intermediate AA12A, Step 1B, first eluting isomer, 4.50 g 7.95 mmol) and LiOH.H₂O (1.66 g, 39.7 mmol) was added solvent dioxane/MeOH (1:1) (159 mL). The mixture was heated to 65° C. and stirred overnight. The mixture was then diluted with H₂O and acidified with 1.0 N HCl to pH-4. The organic solvents were evaporated under reduced pressure and to the residue was added H₂O. The aqueous mixture was then extracted with EtOAc three times, and the combined organic extract was concentrated. The residue was purified on a 120 g SiO₂ gel column eluting with a gradient of 0-70% EtOAc in hexane to provide (S)-6′-chloro-5-(((1R,2R)-2-((S,E)-1-hydroxyhex-2-en-1-yl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid (3.80 g, 7.45 mmol, 94% yield).

Intermediate AA13A (S)-6′-CHLORO-5-(((1R,2R)-2-((S)-1-HYDROXYBUT-3-EN-1-YL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO [BENZO [B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLIC ACID

STEP 1A: (S)-METHYL 6′-CHLORO-5-(((1R,2R)-2-((S)-1-HYDROXYBUT-3-EN-1-YL) CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

An oven-dried 200-mL flask charged with a suspension of (1R,2R)-N-methyl-1-phenyl-1-(((1S,5S,10R)-10-(trimethylsilyl)-9-borabicyclo[3.3.2]decan-9-yl)oxy)propan-2-amine (5.40 g, 14.54 mmol) in Et₂O (73 mL) under argon was cooled to −78° C. and treated with allylmagnesium bromide (13.22 mL, 13.22 mmol) solution, dropwise. The mixture was allowed to warm to ambient temperature and stirred for 1 h. The solution (˜0.17 M; solution A) was then recooled to −78° C.

A separate 200 mL flask charged with ((S)-methyl 6′-chloro-5-(((1R,2R)-2-formylcyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (Intermediate AA11A, Step 20A, 2.0 g, 4.41 mmol) in Et₂O (22.03 mL) under argon was cooled to −78° C. To this solution was added 40 mL of the above-referenced solution A and the resulting mixture was stirred at −78° C. for 40 min. 4-methylmorpholine 4-oxide (3.10 g, 26.4 mmol) was then added and the mixture was allowed to warm to ambient temperature for 10 min. Methanol (10 mL) was added and the volatile organics were evaporated under reduced pressure at ambient temperature. Additional methanol (100 mL) was added and after stirring at ambient temperature for 1 h the mixture was concentrated. The residue was diluted with EtOAc (450 mL), washed with 1N HCl (15 mL), Na₂CO₃ solution (10 mL), and brine (6 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was loaded to a 220 g ISCO gold column and eluted with 0% to 5% EtOAc/hexane, to provide 1.88 g of the title compound as a white solid. m/z (ESI, +ve ion) 496.0 (M+H)⁺.

STEP 1B: (S)-TERTBUTYL 6′-CHLORO-5-(((1R,2R)-2-((S)-1-HYDROXYBUT-3-EN-1-YL) CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO[BENZO[B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLATE

The title compound was synthesized from (S)-tert-butyl 6′-chloro-5-(((1R,2R)-2-formylcyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (Intermediate AA11A, Step 20B; 3.0 g) following the procedure described for Intermediate AA13A, Step 1A. The crude material was purified on a 220 g SiO₂ gel column eluting with 5% EtOAc in hexane over 60 min to provide (S)-tert-butyl 6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxybut-3-en-1-yl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (2.19 g).

STEP 2: (S)-6′-CHLORO-5-(((1R,2R)-2-((S)-1-HYDROXYBUT-3-EN-1-YL)CYCLOBUTYL)METHYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO [BENZO [B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXYLIC ACID

A mixture of (S)-methyl 6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxybut-3-en-1-yl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (from Intermediate AA13A, Step 1A; 1.88 g, 3.79 mmol) and LiOH solution (1M) (34.1 mL, 34.1 mmol) in MeOH (34 mL) and THF (50 mL) was stirred at 65° C. for 50 min. After cooling to ambient temperature, the mixture was acidified with 1N HCl to pH 2 to 3, extracted with EtOAc (350 mL), dried over anhydrous Na₂SO₄ and concentrated to provide 1.82 g of the title compound as a white solid. m/z (ESI, +ve ion) 482.0 (M+H)⁺.

Alternatively, the title compound may be synthesized as follows:

To a solution of (S)-tert-butyl 6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxybut-3-en-1-yl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (Intermediate AA13A, Step 1B; 250 mg, 0.465 mmol) in DCM (3.717 mL) at ambient temperature, TFA (0.929 mL) was added and the reaction mixture was stirred for 4 h. The crude reaction mixture was then concentrated, the residue was taken up in EtOAc, washed once with sat. NaHCO₃, dried over MgSO₄, filtered and concentrated to give a white foam. The crude material was used as such, without further purification.

Intermediate EE11 N,N-BIS(4-METHOXYBENZYL)AMINE

A solution of 4-methoxybenzaldehyde (Spectrochem; 100 g, 734.5 mmol) and 4-methoxybenzyl amine (G.L.R.; 100 g, 734.5 mmol) in toluene (0.8 L) was refluxed at 130° C. using a Dean-Stark apparatus for 6 h. The reaction was monitored by TLC and upon completion, excess solvent was removed under reduced pressure and the residue was dissolved in methanol (0.8 L). The resulting solution was cooled to 0° C. and sodium borohydride (36.12 g, 954.8 mmol) was added in portions. After complete addition, the reaction mixture was stirred for 3 h at ambient temperature. Methanol was removed, and the residue was diluted with H₂O (1.0 L) and EtOAc (2.0 L). The layers were separated and the aqueous layer was extracted with EtOAc (2×1.0 L). The combined organic layer was washed with H₂O, brine, and dried over Na₂SO₄. Solvent was removed under reduced pressure and the crude material obtained was purified by column chromatography over SiO₂ gel (100-200 mesh size) eluting with a gradient of 100% hexane to 25% EtOAc in hexane affording the title compound (160 g, 84.6%) as a colorless but opaque liquid.

Intermediate EE12 N,N-BIS(4-METHOXYBENZYL)METHANESULFONAMIDE

A mixture of methanesulfonamide (Sigma-Aldrich, 5 g, 52.6 mmol), p-methoxybenzyl chloride (14.98 mL, 110 mmol), K₂CO₃ anhydrous (36.3 g, 263 mmol) and potassium iodide (0.873 g, 5.26 mmol) in anhydrous 2-butanone (175 mL) was refluxed (75° C.) overnight. The reaction was monitored by TLC and LC/MS and upon completion, the mixture was cooled to ambient temperature, filtered, washed with Et₂O and concentrated. The crude material (17.54 g, 52.3 mmol, 99% yield) was used with no further purification. MS (ESI, positive ion) m/z: 358.1 (M+Na).

Intermediate EE13 N,N-BIS(4-METHOXYBENZYL)ETHANESULFONAMIDE

To a solution of N,N-bis(4-methoxybenzyl)amine (Intermediate EE11; 200 g, 775.19 mmol) in DCM (2.5 L) was added Et₃N (336.17 mL, 2325.5 mmol), and the reaction mixture was cooled to 0° C. Ethanesulfonyl chloride (95 mL, 1007.75 mmol) was added in drop-wise manner followed by DMAP (19.0 g, 155.03 mmol). The resulting reaction mixture was stirred at ambient temperature for 30 min. The reaction was monitored by TLC and upon completion, the mixture was diluted with H₂O and the layers were separated and the aqueous phase was extracted with DCM (3×1.5 L). The combined organic layer was washed with H₂O, brine, and dried over Na₂SO₄. The solvent was removed under reduced pressure to afford the crude material which was purified by column chromatography over SiO₂ gel (100-200 mesh), eluting with a gradient of 0-12% EtOAc in hexane affording the title compound (145 g, 53.4%) as a white fluffy solid.

Intermediate EE14 N,N-BIS (4-METHOXYBENZYL)PROPANESULFONAMIDE

To a solution of N,N-bis(4-methoxybenzyl)amine (Intermediate EE11; 405 g, 1569.7 mmol) in DCM (4.0 L) was added Et₃N (681.0 mL, 4709.3 mmol), and the reaction mixture was cooled to 0° C. Propanesufonyl chloride (231 mL, 2040.6 mmol) was added in a drop-wise manner followed by DMAP (38.3 g, 313.9 mmol). The resulting mixture was stirred at ambient temperature for 30 min. The reaction was monitored by TLC and upon completion, the mixture was diluted with 2.0 L of H₂O, the layers were separated and the aqueous phase was extracted with DCM (3×2.0 L). The combined organic layer was washed with H₂O, brine, and dried over Na₂SO₄. The solvent was removed under reduced pressure to afford the crude material which was purified by column chromatography over SiO₂ gel (100-200 mesh), eluting with a gradient of 0-12% EtOAc in hexane affording the title compound (300 g, 52.44%) as white fluffy solid.

Intermediate EE15 BUT-3-ENE-1-SULFONAMIDE

STEP 1: SODIUM BUT-3-ENE-1-SULFONATE

A mixture of 4-bromo-1-butene (LLBChem, 3.01 mL, 29.6 mmol) and sodium sulfite (4.11 g, 32.6 mmol) in H₂O (20 mL) was stirred at 110° C. overnight. The reaction was monitored by TLC and upon completion, H₂O was removed under reduced pressure and the residue was triturated with acetone. The solid obtained was filtered to afford the title compound as a white solid (4.53 g) which was used as such in next step.

STEP 2: BUT-3-ENE-1-SULFONAMIDE

A mixture of sodium but-3-ene-1-sulfonate (4.50 g, 28.5 mmol) and phosphorus oxychloride (70 mL) was stirred at 135° C. for 7 h. Phosphorus oxychloride was then removed under reduced pressure to obtain a dark residue containing a white solid. This residue was diluted with MeCN (20 mL), and then filtered to remove the precipitate. The filtrate was cooled to 0° C. and treated with ammonia solution (30% aqueous) (30 mL) dropwise. After complete addition, the reaction was stirred at 0° C. for 30 min. The mixture was diluted with EtOAc (300 mL), washed with brine, and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure and the residue was purified by column chromatography over SiO₂ gel (100-200 mesh; eluting with 1:1 EtOAc/hexane), affording the title compound as a white solid (1.55 g, yield: 40%). MS (ESI, positive ion) m/z: 117.1 (M+1).

Intermediate EE16 N,N-BIS(4-METHOXYBENZYL)BUT-3-ENE-1-SULFONAMIDE

A mixture of but-3-ene-1-sulfonamide (Intermediate EE15; 1.5 g, 11.10 mmol), p-methoxybenzyl chloride (3.76 mL, 27.7 mmol), K₂CO₃ anhydrous (7.67 g, 55.5 mmol) and sodium iodide (0.166 g, 1.110 mmol) in anhydrous 2-butanone (55.5 mL) was refluxed (75° C.) overnight. The reaction was monitored by TLC and LC/MS and upon completion, the mixture was cooled to ambient temperature, filtered, and concentrated. The crude material was absorbed onto a plug of SiO₂ gel and purified by chromatography through SiO₂ gel (100-200 mesh), eluting with 0 to 30% EtOAc in hexane, to provide the title compound (4.10 g, 10.92 mmol, 98% yield) as a colorless oil. MS (ESI, positive ion) m/z: 376.2 (M+1).

Intermediate EE17 (R)-PENT-4-ENE-2-SULFONAMIDE

STEP 1: (S)—N,N-BIS(4-METHOXYBENZYL)PENT-4-ENE-2-SULFONAMIDE AND (R)-N,N-BIS(4-METHOXYBENZYL)PENT-4-ENE-2-SULFONAMIDE

N,N-bis(4-methoxybenzyl)but-3-ene-1-sulfonamide (Intermediate EE16; 50.0 g, 133.2 mmol) was azeotroped with toluene and dried under vacuum for 1 h. THF (890 mL) was added and the mixture was cooled to −78° C. Butyl lithium (2.5 M in hexane, 63.9 mL, 159.9 mmol) was then added and the reaction mixture was stirred at −78° C. for 1 h. This anion solution was added slowly to a solution of MeI (16.8 mL, 266.5 mmol) in THF (300 mL) cooled to −78° C. The resulting reaction mixture was stirred for another 15 min at −78° C. On completion of the reaction (monitored by TLC) the mixture was quenched with sat. NH₄Cl solution and extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to obtain crude material which was purified by column chromatography over SiO₂ gel eluting with 5-10% EtOAc in hexane to provide the title compound as a racemic mixture (22.0 g) of semisolid nature. Separation of the enantiomers by SFC (Column: Chiralpak® AD-H, 50×250 mm, 5 μm; Mobile Phase A: CO₂; Mobile Phase B: Ethanol; Isocratic: 40% B with CO₂ recycler on; Flow Rate: 200 g/min; Loading: 2.0 mL of sample prepared as above (˜100 mg); Detection: UV @ 230 nm; Cycle Time: 5 min; Total Elution Time: 10 min; Instrument: Thar 350 (Lakers)) provided (S)—N,N-bis(4-methoxybenzyl)pent-4-ene-2-sulfonamide as the first eluting isomer (retention time: 2.22 min) and (R)-N,N-bis(4-methoxybenzyl)pent-4-ene-2-sulfonamide as the second eluting isomer (retention time: 2.57 min).

STEP 2: (R)-PENT-4-ENE-2-SULFONAMIDE

To a solution of (R)-N,N-bis(4-methoxybenzyl)pent-4-ene-2-sulfonamide (Intermediate EE17, Step 1, second eluting isomer; 221 mg, 0.567 mmol) in DCM (2.8 mL), was added trifluoroacetic acid (1.7 mL, 22.70 mmol) dropwise (the clear solution very rapidly turned dark). After stirring for 7 h (TLC 30% EtOAc/hexane showed complete loss of starting material) the mixture was diluted with EtOAc, washed with sat. NaHCO₃, back extracted with EtOAc, dried over MgSO₄, and concentrated. The crude material was purified via chromatography (12 g ISCO gold column; 0-40% EtOAc in hexane) to provide (R)-pent-4-ene-2-sulfonamide (70 mg, 0.469 mmol, 83% yield)

Intermediate EE172 (S)-PENT-4-ENE-2-SULFONAMIDE

This intermediate was synthesized from (S)—N,N-bis(4-methoxybenzyl)pent-4-ene-2-sulfonamide (Intermediate EE17, Step 1, first eluting isomer) using the procedure described for Intermediate EE17, Step 2.

Intermediate EE18 (R)-HEX-5-ENE-3-SULFONAMIDE

STEP 1: (S)—N,N-BIS(4-METHOXYBENZYL)HEX-5-ENE-3-SULFONAMIDE AND (R)-N,N-BIS(4-METHOXYBENZYL)HEX-5-ENE-3-SULFONAMIDE

N,N-bis(4-methoxybenzyl)but-3-ene-1-sulfonamide (Intermediate EE16; 40.0 g, 106.6 mmol) was azeotroped in toluene under vacuum for 2 h. THF (700 mL) was added under argon atmosphere and the reaction mixture was cooled to −78° C. Butyl lithium (2.5 M in hexane; 71.6 mL, 127.9 mmol) was added and the reaction mixture was stirred at −78° C. for 1 h. This anion solution was added slowly to a solution of ethyl iodide (36.44 mL, 340.1 mmol) in THF (40 mL) cooled to −78° C. The resulting reaction mixture was then quenched with sat. NH₄Cl solution, allowed to reach ambient temperature and extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to obtain crude material which was purified by column chromatography over SiO₂ gel eluting with 5-10% EtOAc in hexane to provide the title compound as a racemic mixture (24 g) of semisolid nature. MS (ESI, positive ion) m/z; 404.03 (M+1). Separation of the enantiomers by SFC (Sample preparation: 14.4 g/200 mL (72 mg/mL) sample solution in MeOH:DCM (3:1); Column: Chiralpak® AD-H, 30×250 mm, 5 μm; Mobile Phase A: CO₂; Mobile Phase B: MeOH (20 mM NH₃); Isocratic: 50% B, Flow Rate: 100 mL/min; Outlet Pressure: 100 bar; Loading: 1.0 mL of sample solution prepared as above (72 mg); Detection: UV @ 227 nm; Cycle Time: 8 min; Total Elution Time: 17 min; Instrument: Thar 350 SFC) provided (S)—N,N-bis(4-methoxybenzyl)hex-5-ene-3-sulfonamide as the first eluting isomer and (R)-N,N-bis(4-methoxybenzyl)hex-5-ene-3-sulfonamide as the second eluting isomer.

STEP 2: (R)-HEX-5-ENE-3-SULFONAMIDE

This intermediate was synthesized from (R)-N,N-bis(4-methoxybenzyl)hex-5-ene-3-sulfonamide (Intermediate EE18, Step 1, second eluting isomer) using the procedure described for Intermediate EE17, Step 2.

Intermediate EE182 (S)-HEX-5-ENE-3-SULFONAMIDE

This intermediate was synthesized from (S)—N,N-bis(4-methoxybenzyl)hex-5-ene-3-sulfonamide (Intermediate EE18, Step 1, first eluting isomer) using the procedure described for Intermediate EE17, Step 2.

Intermediate EE19 N,N-BIS (4-METHOXYBENZYL)PENT-4-ENE-1-SULFONAMIDE

STEP 1: SODIUM PENT-4-ENE-1-SULFONATE

To a 3 L 3-necked-RBF equipped with a mechanical stirrer, a N₂ gas inlet, a condenser, and a temperature probe was charged 5-bromo-1-pentene (Sigma Aldrich, 200 g, 1342 mmol), sodium sulfite (Strem Chemicals; 186 g, 1476 mmol), and H₂O (400 mL). The mixture was heated to reflux (set at 100° C. and refluxed at 93-94° C.) 4 h; aliquot NMR showed >95% conversion. The mixture was concentrated and azeotroped with acetone to remove H₂O. The crude solid was washed with acetone and filtered to afford sodium pent-4-ene-1-sulfonate (350 g, 2033 mmol).

STEP 2: PENT-4-ENE-1-SULFONAMIDE

To a 3 L 3-necked-RBF equipped with a mechanical stirrer, a N₂ gas inlet, a condenser, and a temperature probe was charged sodium pent-4-ene-1-sulfonate (100 g, 581 mmol) (˜150 g of crude material from Step 1) and phosphorus oxychloride (Sigma Aldrich; 532 mL, 5808 mmol). The mixture was heated to 90° C. for 18 h after which the reaction was filtered and the solid was washed with MeCN. The organic solution was concentrated and azeotroped with MeCN to remove POCl₃ to afford 85 g pent-4-ene-1-sulfonyl chloride intermediate. This material (solution in 300 mL MeCN) was charged onto a 1 L 3-necked-RBF equipped with a mechanical stirrer, a N₂ gas inlet, a condenser, and a temperature probe. The reaction was cooled to 0-5° C. and NH₄OH (Sigma Aldrich; 28% NH₃; 404 mL, 2904 mmol) was added slowly over 30 min. The reaction was stirred at 0-5° C. for 1 h, after which EtOAc (300 mL) was added and the mixture was extracted with EtOAc and concentrated to afford pent-4-ene-1-sulfonamide (50 g, 335 mmol, 57.7% yield) as a brown oil.

STEP 3: N,N-BIS(4-METHOXYBENZYL)PENT-4-ENE-1-SULFONAMIDE

The title compound was synthesized from pent-4-ene-1-sulfonamide (4.5 g, 30.2 mmol) following the procedure described for Intermediate EE16. Purification of the crude material provided N,N-bis(4-methoxybenzyl)pent-4-ene-1-sulfonamide (11.4 g, 29.3 mmol, 97% yield) as a colorless oil.

Intermediate EE20 (R)-HEX-5-ENE-2-SULFONAMIDE

STEP 1: (S)—N,N-BIS(4-METHOXYBENZYL)HEX-5-ENE-2-SULFONAMIDE AND (R)-N,N-BIS(4-METHOXYBENZYL)HEX-5-ENE-2-SULFONAMIDE

A solution of N,N-bis(4-methoxybenzyl)ethanesulfonamide (Intermediate EE13; 140.0 g, 400.64 mmol) in THF (1.4 L, THF was purged with argon for 15 min before using) was cooled to −78° C. and butyl lithium solution (2.6 M in hexane, 200.0 mL, 520.83 mmol) was added drop-wise. The resulting solution was stirred at −78° C. for 10 min, and 4-bromo-1-butene (73.2 mL, 721.15 mmol) was added over 2 min. After 5 min, the reaction was allowed to reach ambient temperature and stir for 1 h. The reaction was monitored by TLC and upon completion, the mixture was quenched with sat. NH₄Cl solution (400 mL) and the resulting aqueous layer was extracted with EtOAc (2×1.0 L). The combined organic layer was washed with brine and dried over Na₂SO₄. The solvent was removed under reduced pressure to afford the crude material which was purified by column chromatography (SiO₂ gel 100-200 mesh) eluting with a gradient of 0-4% acetone in hexane affording the title compound (racemic mixture, 80.0 g, 49.5%) as a colorless thick oil. MS (ESI, positive ion) m/z: 404.25 (M+1). Separation of the enantiomers by SFC (Sample preparation: 75 g/1.5 L (50 mg/mL) sample solution in MeOH; Column: Chiralpak® IF, 21×250 mm, 5 μm; Mobile Phase A: CO₂; Mobile Phase B: MeOH (0.2% DEA); Isocratic: 40% B; Flow Rate: 80 mL/min; Outlet Pressure: 100 bar; Loading: 3.0 mL of sample solution prepared as above (150 mg); Detection: UV at 225 nm; Cycle Time: 3.9 min; Total Elution Time: 6 min; Instrument: Thar 80 SFC) provided (S)—N,N-bis(4-methoxybenzyl)hex-5-ene-2-sulfonamide as the first eluting isomer and (R)-N,N-bis(4-methoxybenzyl)hex-5-ene-2-sulfonamide as the second eluting isomer.

STEP 2: (R)-HEX-5-ENE-2-SULFONAMIDE

The title compound was synthesized from (R)-N,N-bis(4-methoxybenzyl)hex-5-ene-2-sulfonamide (Intermediate EE20, Step 1, second eluting isomer) using the procedure described for Intermediate EE17, Step 2.

Intermediate EE202 (S)-HEX-5-ENE-2-SULFONAMIDE

The title compound was synthesized from (S)—N,N-bis(4-methoxybenzyl)hex-5-ene-2-sulfonamide (Intermediate EE20, Step 1, first eluting isomer) using the procedure described for Intermediate EE17, Step 2.

Intermediate EE21 (R)-HEPT-6-ENE-3-SULFONAMIDE

STEP 1: (S)—N,N-BIS(4-METHOXYBENZYL)HEPT-6-ENE-3-SULFONAMIDE AND (R)-N,N-BIS(4-METHOXYBENZYL)HEPT-6-ENE-3-SULFONAMIDE

The title compound was synthesized from N,N-bis(4-methoxybenzyl)propanesulfonamide (Intermediate EE14) using the procedure described for Intermediate AA20, Step 1. Separation of the enantiomers by SFC (Sample preparation: 40.55 g/170 mL (238.5 mg/mL) sample solution in MeOH; Column: Chiralpak® AD-H, 50×150 mm, 5 μm; Mobile Phase A: CO₂; Mobile Phase B: MeOH (20 mM NH₃); Isocratic: 50% B; Flow Rate: 190 mL/min; Outlet Pressure: 100 bar; Loading: 1.5 mL of sample solution prepared as above (357.8 mg); Detection: UV at 227 nm; Cycle Time: 17.5 min; Total Elution Time: 21 min; Instrument: Thar 350 SFC) provided (S)—N,N-bis(4-methoxybenzyl)hept-6-ene-3-sulfonamide as the first eluting isomer and (R)-N,N-bis(4-methoxybenzyl)hept-6-ene-3-sulfonamide as the second eluting isomer.

STEP 2: (R)-HEPT-6-ENE-3-SULFONAMIDE

The title compound was synthesized from (R)-N,N-bis(4-methoxybenzyl)hept-6-ene-3-sulfonamide (Intermediate EE21, Step 1, second eluting isomer) using the procedure described for Intermediate EE17, Step 2.

Intermediate EE212 (S)-HEPT-6-ENE-3-SULFONAMIDE

The title compound was synthesized from (S)—N,N-bis(4-methoxybenzyl)hept-6-ene-3-sulfonamide (Intermediate EE21, Step 1, first eluting isomer) using the procedure described for Intermediate EE17, Step 2.

Intermediate EE22 (2R,3 S)-3-METHYLHEX-5-ENE-2-SULFONAMIDE

STEP 1: (4S,5S)-4,5-DIMETHYL-1,3,2-DIOXATHIOLANE 2,2-DIOXID

To a 500-mL, 3-necked-RBF (equipped with a H₂O-cooled reflux condenser and an HCl trap) was added (2s,3s)-(+)-2,3-butanediol (Aldrich; 15.00 mL, 166 mmol) and CCl₄ (120 mL). SOCl₂, reagentplus (14.57 mL, 200 mmol) was then added drop wise via a syringe over a period of 20 min and the resulting mixture was heated to 98° C. for 45 min, then allowed to cool to rt. The reaction mixture was then cooled in an ice/H₂O bath, MeCN (120 mL) and H₂O (150 mL) were added followed by ruthenium(III) chloride (0.035 g, 0.166 mmol). Sodium periodate (53.4 g, 250 mmol) was then added slowly portion wise over 30 min. The resulting biphasic brown mixture was stirred vigorously while allowed to reach rt for a period of 1.5 h (internal temperature never increased above rt). TLC (50% EtOAc in heptanes) showed complete conversion. The crude mixture was then poured into ice H₂O and extracted twice with 300 mL of Et₂O. The combined organic layers were washed once with 200 mL of sat. sodium bicarbonate, washed once with 200 mL of brine, dried over Na₂SO₄, and concentrated by rotary evaporation to give (4S,5S)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide (21.2 g, 139 mmol) as a red oil.

STEP 2: (2S,3S)-3-METHYLHEX-5-EN-2-OL

To a 500 mL flask was added (4S,5S)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide (from Intermediate EE22, Step 1; 21.2 g, 139 mmol) and THF (220 mL) at which time the solution was cooled to −78° C. and was subjected to 3 cycles of evacuation/back-filling with argon. To the solution was added dilithium tetrachlorocuprate(ii), 0.1M solution in THF (69.7 mL, 6.97 mmol). The resulting mixture was stirred at −78° C. for 30 min and then allylmagnesium bromide, 1.0 M solution in Et₂O (397 mL, 397 mmol) was added slowly via cannula over 80 min. The resulting mixture was stirred at 0° C. for 4 h. The mixture was quenched with 200 mL H₂O and allowed to reach rt at which time the volatiles were removed by rotary evaporation. To the aqueous residue was then added 50% H₂SO₄ (150 mL), the mixture was stirred for 5 min, Et₂O was then added (400 mL) and the mixture was stirred vigorously at rt overnight. The layers were separated; the aqueous layer was extracted with 300 mL Et₂O and the combined organic layers were washed with 300 mL of sat. NaHCO₃, dried over Na₂SO₄, filtered and concentrated by rotary evaporation to give (2S,3S)-3-methylhex-5-en-2-ol (6.7 g, 58.7 mmol) as a clear oil.

STEP 3: 2-(((2R,3S)-3-METHYLHEX-5-EN-2-YL)THIO)PYRIMIDINE

To a 2000 mL dry RBF containing a stirring solution of tributylphosphine (57.7 mL, 231 mmol) in 1000 mL degassed THF (sparged with argon for 30 min plus 5 cycles of pump/add argon) at 0° C. was added diethyl azodicarboxylate (40 wt. % solution in toluene; 103 mL, 262 mmol) drop wise under an atmosphere of argon. A solution of (2S,3S)-3-methylhex-5-en-2-ol (from Intermediate EE22, Step 2; 17.6 g, 154 mmol; dried over Na₂SO₄) was added drop wise as a solution in 50 mL of THF to the solution of phosphine/diethyl azodicarboxylate complex, via syringe-filter (0.45 um). The resulting ROH/diethyl azodicarboxylate/tri-n-butylphosphine mixture was aged at zero degrees for 15 min (solution turned light orange), at which time pyrimidine-2-thiol (49.3 g, 439 mmol) was added gradually to the top of the reaction vessel (as a solid) under positive argon pressure. The reaction was stirred at 0° C. for 1 h then at rt 15 h (reaction not complete at 12 h by LC/MS). The crude reaction was then filtered to remove excess pyrimidine-2-thiol, diluted with 1000 mL of EtOAc, extracted twice with 500 mL of 1 N K₂CO₃, and once with 500 mL of brine. The aqueous layer was back extracted with 300 mL of EtOAc and the combined organic layers were dried over Na₂SO₄. The organic solution was then filtered, the solvent removed by rotary evaporation and the crude filtered to remove the (E)-diethyl diazene-1,2-dicarboxylate generated in the reaction. The filtrate (125 g) was passed through a SiO₂ plug (500 g SiO₂, eluting with 2 L of DCM) to give 75 g of crude product after solvent removal. The crude product was purified again on a Combiflash® (125 g gold SiO₂ column), eluting with 10% EtOAc in heptanes to give 2-(((2R,3S)-3-methylhex-5-en-2-yl)thio)pyrimidine (20.37 g, 98 mmol) as a light yellow oil.

STEP 4: 2-(((2R,3S)-3-METHYLHEX-5-EN-2-YL)SULFONYL)PYRIMIDINE

To a 500 mL 3-necked-RBF with a reflux condenser was added phenylphosphonic acid (3.95 g, 24.96 mmol), sodium tungstate oxide dihydrate (8.23 g, 24.96 mmol), tetrabutylammonium sulfate (50 wt. % solution in H₂O, 28.7 mL, 24.96 mmol), a catalytic amount of hydrogen peroxide (30% in H₂O, 12.75 mL, 125 mmol), toluene (200 mL) and 2-(((2R,3S)-3-methylhex-5-en-2-yl)thio)pyrimidine (from Intermediate EE22, Step 3; 52 g, 250 mmol). The reaction was stirred at 45° C. for 5 min at which time hydrogen peroxide 30% in H₂O (58.6 mL, 574 mmol) was added portion wise (10 mL at a time). Five min after the first portion of hydrogen peroxide was added, an exotherm was observed (65° C.), the reaction was taken out of oil bath, the addition was stopped and the flask placed in a H₂O bath until temperature stabilizes. The flask was taken out of the H₂O bath and the portion wise addition of hydrogen peroxide was continued at a rate in which the internal temperature stayed between 45° C. and 55° C. (˜40 min). An ice bath was utilized if the temperature went above 60° C. and an oil bath was used if the temperature fell below 45° C. The reaction was then stirred at 45° C. for 1 h. The reaction was diluted with 1400 mL of EtOAc and extracted two times with 500 mL of H₂O and once with 500 mL of brine. The organic layer was dried over Na₂SO₄, filtered, concentrated, and the crude purified on a Combiflash® (330 g gold SiO₂ column per 30 grams of crude), eluting with 0%-50% EtOAc in heptanes to give 2-(((2R,3S)-3-methylhex-5-en-2-yl)sulfonyl)pyrimidine (55.7 g, 232 mmol) as a light yellow oil.

STEP 5: SODIUM (2R,3S)-3-METHYLHEX-5-ENE-2-SULFINATE

To a solution of 2-(((2R,3S)-3-methylhex-5-en-2-yl)sulfonyl)pyrimidine (from Intermediate EE22, Step 4; 52 g, 216 mmol) in MeOH (400 mL) at rt was added sodium methoxide solution (51.0 mL, 223 mmol) over 70 min. The sodium methoxide was added portion wise, the internal temperature was monitored, and the addition was slowed or the reaction was cooled in a H₂O bath, never letting the internal temperature exceeded 30° C. The mixture was concentrated by rotary evaporation and the waxy solid was triturated with MTBE (add 200 mL MTBE, stir for 1 h using a spatula to break up clumps), filtered (use a stream of N₂ over filter cake), and washed with 100 mL of cold MTBE to obtain sodium (2R,3S)-3-methylhex-5-ene-2-sulfinate (46 g, 250 mmol) as a an off white solid.

STEP 6: (2R,3S)-3-METHYLHEX-5-ENE-2-SULFONAMIDE

To a 1000 mL 3-necked-RBF was added sodium (2R,3S)-3-methylhex-5-ene-2-sulfinate (from Intermediate EE22, Step 5; 46 g, 225 mmol), 500 mL of H₂O and KOAc (44.1 g, 449 mmol) at rt. The flask was place in a 45° C. oil bath and hydroxylamine-O-sulfonic acid (21.09 g, 187 mmol) was added portion wise over 90 min. The internal temperature of the reaction was monitored and the reaction was removed from the oil bath (if needed) to control exotherm (Tmax=55° C.). The reaction was monitored by LC/MS every 10 min and was complete after the addition of 0.83 eq. of hydroxylamine-O-sulfonic acid. The mixture was then cooled to rt and was extracted with 1000 mL of EtOAc. The organic phase was extracted three times with 500 mL of 1 N HCl, two times with 300 mL of sat. sodium bicarbonate, once with 200 mL of brine, dried over Na₂SO₄, filtered, and concentrated by rotary evaporation to provide (2R,3S)-3-methylhex-5-ene-2-sulfonamide (32 g, 181 mmol) as a white solid.

Intermediate 1 (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0³′6.0^(19,24)]PENTACOSA [8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE

STEP 1: (S)-6′-CHLORO-5-(((1R,2R)-2-((S)-1-HYDROXYALLYL)CYCLOBUTYL)METHYL)-N-(((2R,3 S)-3-METHYLHEX-5-EN-2-YL)SULFONYL)-3′,4,4′,5-TETRAHYDRO-2H,2′H-SPIRO [BENZO [B][1,4]OXAZEPINE-3,1′-NAPHTHALENE]-7-CARBOXAMIDE

DMAP (3.42 g, 28.0 mmol) was added to a solution of (S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid (Intermediate AA11A; 7.7 g, 16.45 mmol) and (2R,3S)-3-methylhex-5-ene-2-sulfonamide (Intermediate EE22; 5.83 g, 32.9 mmol) in DCM (411 mL) cooled to 0° C. EDC hydrochloride (6.31 g, 32.9 mmol) was then added slowly portionwise. The mixture was stirred while allowing to reach ambient temperature overnight. The mixture was washed with 1N HCl and brine and the aqueous layer was back-extracted with EtOAc. The combined organics were dried over MgSO₄, filtered and concentrated. The yellow oily residue was loaded onto a 220 ISCO gold column and purified eluting with 0% to 20% EtOAc (containing 0.3% AcOH)/heptanes, to provide (S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-N-(((2R,3 S)-3-methylhex-5-en-2-yl)sulfonyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxamide (7.89 g, 12.58 mmol, 76% yield).

STEP 2: (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0^(3,6).0^(19,24)]PENTACOSA [8,16,18,24]TETRAEN]-15′-ONE 13′,13′-DIOXIDE

To a 20 L reactor blanketed in argon was charged 14 L of 1,2-DCE. (S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-N-(((2R,3 S)-3-methylhex-5-en-2-yl)sulfonyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxamide (18.75 g, 29.9 mmol) was added as a solution in 400 mL 1,2-DCE followed by a 400 mL rinse. The reactor was sealed and purged with argon. Hoveyda-Grubbs II (1.873 g, 2.99 mmol) was added as a solution in 150 mL of 1,2-DCE followed by a 50 mL rinse. The reactor was heated to 60° C. over 1 h with an argon sweep of the headspace and held at temperature for 9 h. The reaction was quenched by the addition of 2-(2-(vinyloxy)ethoxy)ethanol (1.501 g, 11.36 mmol), cooled to ambient temperature, and concentrated to ˜200 mL volume by rotary evaporation. The reaction was transferred to a 1 L RBF and diluted to 500 mL volume with 1,2-DCE. The reaction was treated with 52 g of Silicycle Si-Thiol (SiliCycle Inc., Quebec City, Quebec CANADA Cat# R51030B) with stirring for 9 h at 40° C., filtered and rinsed with 2×65 mL DCM. The solution was passed through a Whatman GF/F filter cup (GE Healthcare Bio-Sciences Pittsburgh, Pa., USA) to afford a transparent yellow solution. The reaction was concentrated to afford a crude product mass of 27.4 g. The residue was slurried in 250 mL IPAc and evaporated to dryness three times. The reaction was suspended in 270 mL IPAc, heated to dissolution, allowed to cool to ambient temperature, and stirred for 18. The solids were filtered and washed with 65 mL IPAc. The solid was air-dried for 30 min then placed under high vacuum for 3 h to afford 12.56 g of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2h,15′h-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0^(3,6).0^(19,24)]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide which is 91.7% by weight. ¹H NMR (500 MHz, CD₂Cl₂) δ 8.06 (s, 1H), 7.71 (d, J=8.56 Hz, 1H), 7.17 (dd, J=8.44, 2.32 Hz, 1H), 7.09 (d, J=2.20 Hz, 1H), 6.91 (s, 3H), 5.81 (ddd, J=14.92, 7.82, 4.16 Hz, 1H), 5.71 (dd, J=15.41, 8.31 Hz, 1H), 4.16-4.26 (m, 2H), 3.83 (d, J=14.43 Hz, 1H), 3.69 (d, J=14.43 Hz, 1H), 3.25 (d, J=14.43 Hz, 1H), 3.04 (dd, J=15.28, 9.66 Hz, 1H), 2.68-2.84 (m, 2H), 2.41 (app qd, J=9.80, 3.70 Hz, 1H), 2.25-2.34 (m, 1H), 1.93-2.00 (m, 5H), 1.74-2.11 (m, 9H), 1.62-1.73 (m, 1H), 1.43 (d, J=7.09 Hz, 3H) 1.35-1.42 (m, 1H) 1.03 (d, J=6.60 Hz, 3H). MS (ESI, +ve ion) m/z 599.2 (M+H)⁺.

Intermediate 2 (1S,3′R,6′R,7′S, 11′S,12′R)-6-CHLORO-7′-HYDROXY-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0^(3,6).0^(19,24)]PENTACOSA [16,18,24]TRIEN]-15′-ONE 13′,13′-DIOXIDE

A mixture of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2h, 15′h-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0^(3,6).0^(19,24)]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (Intermediate 1, 7.5 mg, 0.013 mmol) and platinum (IV) oxide (2.84 mg, 0.013 mmol) in EtOAc (1.536 mL) was stirred under an atmosphere of H₂ (balloon) at ambient temperature for 45 min. The reaction mixture was then filtered through a syringe filter. The crude material was purified by chromatography through a Redi-Sep® pre-packed SiO₂ gel column (4 g), eluting with 15% to 50% EtOAc (containing 0.3% AcOH)/heptanes, to provide the title product. ¹H NMR (400 MHz, CD₂Cl₂) δ 8.24 (br. s., 1H), 7.71 (d, J=8.4 Hz, 1H), 7.17 (dd, J=2.3, 8.4 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 7.06 (d, J=1.8 Hz, 1H), 6.99 (dd, J=2.0, 8.0 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 4.10 (s, 2H), 4.05 (ddd, J=1.2, 7.2, 14.3 Hz, 1H), 3.82 (d, J=15.3 Hz, 1H), 3.74-3.69 (br. S., 1H), 3.68 (d, J=14.3 Hz, 1H), 3.23 (d, J=14.3 Hz, 1H), 3.06 (dd, J=7.3, 15.4 Hz, 1H), 2.84-2.68 (m, 2H), 2.38 (d, J=3.5 Hz, 2H), 2.08-1.96 (m, 3H), 1.96-1.88 (m, 1H), 1.88-1.75 (m, 2H), 1.74-1.56 (m, 4H), 1.47 (d, J=12.1 Hz, 2H), 1.40 (d, J=7.2 Hz, 3H), 1.32-1.26 (m, 2H), 1.23-1.15 (m, 2H), 1.00 (d, J=6.8 Hz, 3H). MS (ESI, +ve ion) m/z 601.2 (M+H)⁺.

Intermediate 3 (1S,3′R,6′R,8′E,12′S)-6-CHLORO-12′-METHYL-3,4-DIHYDRO-2H,7′H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0³′6.0¹⁹²⁴]PENTACOSA [8,16,18,24]TETRAENE]-7′,15′-DIONE 13′,13′-DIOXIDE

The allyl alcohol (310 mg, 0.520 mmol, Intermediate 1) was dissolved in DCM (6.0 mL) and cooled to 0° C. Dess-Martin periodinane (270 mg, 0.63 mmol) was then added and the reaction mixture was stirred for 1.5 hours. Another 90 mg of Dess-Martin reagent was added at 0° C. and stirred for an additional 45 minutes. The reaction was quenched with 20 mL of 1M Na₂S₂O₃ and allowed to warm to room temperature. The mixture was extracted (3×40 mL) with DCM. The combined organic layers were washed with water (1×30 mL) and then dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica, 10 to 100% EtOAc (+0.3% HOAc):Hexanes) to give (1S,3′R,6′R,8′E,12′S)-6-chloro-12′-methyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0^(3,6).0^(19,24)]pentacosa[8,16,18,24]tetraene]-7′,15′-dione 13′,13′-dioxide (230 mg, 0.385 mmol, 74.0% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.32-9.05 (m, 1H), 7.69-7.90 (m, 1H), 7.35-7.48 (m, 1H), 7.17-7.27 (m, 1H), 7.06-7.16 (m, 1H), 6.81-6.99 (m, 2H), 6.59-6.72 (m, 1H), 5.93 (d, J=15.65 Hz, 1H), 4.01-4.24 (m, 3H), 3.74-3.97 (m, 3H), 3.26 (d, J=14.48 Hz, 1H), 2.92-3.16 (m, 2H), 2.69-2.89 (m, 2H), 1.70-2.26 (m, 9H), 1.48-1.56 (m, 3H), 1.35-1.46 (m, 1H), 1.29 (t, J=7.14 Hz, 1H), 1.07-1.19 (m, 3H). m/z (ESI, +ve ion) 596.7 (M+H)⁺.

Intermediate 4 (1S,3′R,6′R, 11′S,12′R)-6-CHLORO-11′,12′-DIMETHYL-3,4-DIHYDRO-2H,7′H,15′H-SPIRO[NAPHTHALENE-1,22′-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0³′6.0¹⁹²⁴]PENTACOSA [16,18,24]TRIENE]-7′,15′-DIONE 13′,13′-DIOXIDE

To a solution of (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-hydroxy-11′,12′-dimethyl-3,4-dihydro-2h, 15′h-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.03,6˜.019,24]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (1.20 g, 2.02 mmol, Intermediate 1) in EtOAc (50 mL) was added platinum (IV) oxide (92 g, 0.40 mmol) and the reaction was fitted with a H₂ balloon and stirred vigorously for 15 h. The reaction mixture was filtered through Celite and concentrated. The concentrate was dissolved in dichloromethane (20 mL) and then Dess-Martin periodinane (0.95 g, 2.2 mmol) was added in four portions over 5 min at 0° C. After the reaction was stirred at 0° C. for 15 min, the reaction was quenched with 1N sodium thiosulfate solution at 0° C. (10 mL) and stirred vigorously at rt for 30 min. Then the reaction mixture was extracted (EtOAc). The separated organic layer was washed (brine), dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by silica-gel chromatography (0% to 25% EtOAc/hexane, 0.1% AcOH) to provide (1S,3′R,6′R, 11′S,12′R)-6-chloro-11′,12′-dimethyl-3,4-dihydro-2H,7′H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo [14.7.2.0^(3,6).0^(19,24)]pentacosa[16,18,24]triene]-7′,15′-dione 13′,13′-dioxide as a solid (0.85 g, 70% yield). MS (ESI, +ve ion) m/z 599.2 (M+H)⁺.

Biological Assays Cell Free Mcl-1:Bim Affinity Assay (Mcl-1 HTRF)

The inhibition of the Mcl-1/Bim interaction was measured using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. The recombinant human Mcl-1 (C-terminally 6xHis tagged Mcl-1 containing residues 171-327) was generated at Amgen Inc (Thousand Oaks, Calif.). A biotinylated peptide derived from human Bim (residues 51-76) was purchased from CPC Scientific (San Jose, Calif.). The TR-FRET assay was conducted in a 384-well white OptiPlate™ (PerkinElmer, Waltham, Mass.) in a total volume of 40 μL. The reaction mixture contained 0.1 nM Mcl-1(171-327), 0.05 nM biotin-Bim(51-76), 0.05 nM LANCE® Eu-W1024 Anti-6xHis (PerkinElmer), 0.072 nM Streptavidin-Xlent (Cisbio, Bedford, Mass.), and serially diluted test compounds in the binding buffer of 20 mM Hepes, pH 7.5, 150 mM NaCl, 0.016 mM Brij®35, and 1 mM dithiothreitol. Test compounds were pre-incubated with Mcl-1(171-327) and biotin-Bim (51-76) for 60 min before addition of the detection mixture (LANCE®Eu-W1024 Anti-6xHis and Streptavidin-Xlent). The reaction plates were further incubated overnight and then were read on an Envision® multimode reader (PerkinElmer). Fluorescence signals were measured at 620 nm (40-nm bandwidth) and 665 nm (7.5-nm bandwidth) with a 60 s delay after excitation at 320 nm (75-nm bandwidth). The signal ratio at 665/620 nm corresponded to the Mcl-1/Bim interaction and was used in all data analyses. The IC₅₀ values of test compounds were determined from duplicate data by analyzing competition curves using a four-parameter sigmoidal model in GraphPad Prism (GraphPad Software, San Diego, Calif.) or in Genedata Screener® (Genedata, Basel, Switzerland).

Cell Viability Assay (OPM-2 10 FBS)

The human multiple myeloma cell line, OPM-2, was cultured in complete growth medium containing RPMI 1640 and 10% fetal bovine serum (FBS). Cells were seeded into 384-well plates at 3000 cells/well density in complete growth medium containing 10% FBS, and incubated for 16 h with serially diluted test compounds in a 37° C. incubator with 5% CO₂. Cell viability was tested using CellTiter-Glo® assay (Promega, Madison, Wis.) according to the manufacturer recommendations. Luminescence was determined using an EnVision® Multilabel plate reader 25 min after the addition of detection reagent. IC₅₀ values were then calculated with Xlfit using a logistical 4-parameter fit model in GraphPad Prism (GraphPad Software, San Diego, Calif.) or in Genedata Screener® (Genedata, Basel, Switzerland).

Results for compounds tested in these biological assays are set forth below in Table 4 and Table 5.

TABLE 4 Mcl-1 OPM-2 Example HTRF IC₅₀ 10% FBS IC₅₀ Number (μM) IP (μM) 1 0.000086 0.085 2 0.000109 0.076 3 0.000094 0.060 4 0.000116 0.094 5 0.000098 0.040 6 0.000079 0.076 7 0.000058 0.025 8 0.000053 0.025 9 0.000078 0.050 10 0.000103 0.075 11 0.000098 0.051 12 0.000072 0.022 13 0.000094 0.063 14 0.000080 0.059 15 0.000119 0.071 16 0.000065 0.053 17 0.000073 0.034 18 0.000060 0.022 19 0.000125 0.047 20 0.000082 0.022 21 0.000156 0.047 22 0.000669 2.230 23 0.000071 0.024 24 0.000086 0.035 25 0.000113 0.041 26 0.000079 0.032 27 0.000095 0.029 28 0.000082 0.111 29 0.000249 0.186 30 0.000110 0.166 31 0.000184 0.216 32 0.000128 0.147 33 0.008250 5.570 34 0.000495 0.379 35 0.000218 0.235 36 0.000554 0.518 37 0.000615 0.643 38 0.000342 0.489 39 0.000377 0.389 40 0.000444 0.571 41 0.000642 0.810 42 0.000170 0.149 43 0.001640 0.888 44 0.000288 1.360 45 0.000245 0.891 46 0.000107 0.167 47 0.000131 0.285 48 0.000140 0.407 49 0.000087 0.185 50 0.000736 1.530 51 0.000072 0.099 52 0.000522 0.330 53 0.000336 0.290 54 0.000173 0.129 55 0.000162 0.080 56 0.000083 0.079 57 0.000258 0.090 58 0.000719 0.095 59 0.000116 0.048 60 0.000287 0.129 61 0.000075 0.124 62 0.000115 0.110 63 0.000173 0.582 64 0.000126 0.201 65 0.000451 1.500 66 0.000246 0.318 67 0.000197 0.149 68 0.000397 1.520 69 0.003830 1.480 70 0.001326 3.140 71 0.000371 1.140 72 0.000800 0.185 73 0.000609 0.129 74 0.002290 3.360 75 0.002047 1.610 76 0.003815 0.670 77 0.001217 0.415 78 0.000573 0.175 79 0.001800 0.245 80 0.001550 0.205 81 0.000140 0.112 82 0.000394 0.520 83 0.000223 0.245 84 0.000106 0.061 85 0.000491 0.274 86 0.00390  7.95 87 0.000127 0.141 88 0.000139 0.074 89 0.003750 8.210 90 0.004660 8.980 91 0.000203 0.559 92 0.000143 0.199 93 0.000530 0.924 94 0.000191 0.140 95 0.000189 0.338 96 0.000114 0.111 97 0.000299 0.228 98 0.000373 0.183 99 0.000243 0.310 100 0.000188 1.650 101 0.000196 0.263 102 0.000182 0.416 103 0.000452 0.737 104 0.001119 0.782 105 0.000423 0.655 106 0.000299 0.308 107 0.001138 0.872 108 0.000198 0.116 109 0.001042 0.916 110 0.000505 1.720 111 0.000362 0.301 112 0.000617 0.654 113 0.001190 1.330 114 0.000104 0.068 115 0.001370 0.686 116 0.000244 0.387 117 0.000352 0.358 118 0.000215 0.558 119 0.000465 0.694 120 0.000263 0.304 121 0.000084 0.120 122 0.000087 0.138 123 0.000205 0.228 124 0.000646 0.598 125 0.006100 1.475 126 0.000627 0.900 127 0.000395 6.120 128 0.000256 19.600 129 0.001694 2.630 130 0.000920 1.580 131 0.000249 0.482 132 0.000613 0.263 133 0.000189 0.136 134 0.004640 3.000 135 0.008175 >33.3 136 0.004700 1.020 137 0.004740 1.150 138 0.026700 >33.3 139 0.032017 >33.3 140 0.000098 0.125 141 0.000152 0.367 142 0.000157 0.174 143 0.000432 0.219 144 0.000271 0.163 145 0.000124 0.113 146 0.000337 0.150 147 0.000376 0.157 148 0.001200 1.610 149 0.000128 0.119 150 0.000193 0.245 151 0.000843 0.462 152 0.000092 0.110 153 0.000960 10.800 154 0.000197 0.554 155 0.000228 0.378 156 0.000096 0.062 157 0.000126 0.121 158 0.000092 0.018 159 0.000096 0.079 160 0.000221 0.148 161 0.000094 0.113 162 0.000072 0.055 163 0.000179 0.130 164 0.000047 0.031 165 0.000190 0.182 166 0.000107 0.050 167 0.000086 0.052 168 0.000138 0.052 169 0.000140 0.074 170 0.000131 0.075 171 0.000074 0.122 172 0.000137 0.055 173 0.000173 0.323 174 0.000322 0.639 175 0.000069 0.064 176 0.000118 0.149 177 0.000153 0.615 178 0.000177 0.071 179 0.000072 0.036 180 0.000106 0.081 181 0.000324 0.074 182 0.000171 0.088 184 0.000068 0.017 185 0.000170 1.060 186 0.000255 0.431 187 0.000066 0.043 188 0.000084 0.038 189 0.000084 0.033 190 0.000087 0.053 191 0.000096 0.042 192 0.000078 0.065 193 0.000096 0.023 194 0.000148 0.054 195 0.000214 0.065 196 0.000470 0.304 197 0.000364 0.129 198 0.000181 1.314 199 0.000119 0.208 200 0.000315 0.583 201 0.000119 0.244 202 0.000058 0.142 203 0.000113 0.112 204 0.000230 0.319 205 0.000263 0.437 206 0.000223 6.300 207 0.000137 0.395 208 0.000099 0.368 209 0.000552 0.437 210 0.000138 0.185 211 0.000147 0.156 212 0.000122 0.307 213 0.000239 0.400 214 0.000071 0.084 215 0.000149 0.107 216 0.000490 0.183 217 — 0.192 218 0.000142 0.092 219 0.000073 0.047 220 0.000052 0.042 221 0.000069 0.120 222 0.000080 0.118 223 0.000251 0.258 224 0.000127 0.157 225 0.000087 0.280 226 0.000057 0.049 227 0.000207 0.131 228 0.000200 0.0931 229 0.000619 0.096 230 0.000051 0.070 231 0.000061 0.098 232 0.000141 0.200 233 0.000516 0.202 234 0.000163 0.071 235 0.000180 0.120 236 0.000097 0.087 237 0.000130 0.064 238 0.000176 0.076 239 0.000146 0.148 240 0.000128 0.141 241 0.000150 0.137 242 0.000249 0.791 243 0.000078 0.106 244 0.001654 0.638 245 0.000120 0.058 246 0.000099 0.138 247 0.000129 0.107 248 0.000222 0.518 249 0.000063 0.114 250 0.000071 0.047 251 0.002260 3.870 252 0.001375 1.800 253 0.000804 0.887 254 0.001200 0.544 255 0.001740 1.480 256 0.000433 1.640 257 0.000403 0.981 258 0.000069 0.095 259 0.000230 0.254 260 0.000083 0.103 261 0.000153 0.146 262 0.000093 0.089 263 0.000147 0.124 264 0.000396 0.771 265 0.000423 0.578 266 0.000282 0.723 267 0.000297 0.250 268 0.000065 0.072 269 0.000104 0.086 270 0.000035 4.860 271 0.000031 0.359 272 0.000144 0.137 273 0.000494 0.501 274 0.000285 0.232 275 0.000176 0.082 276 0.000096 0.110 277 0.000058 0.057 278 0.000039 0.574 279 0.000084 0.453 280 0.000052 0.073 281 0.000181 0.152 282 0.000118 0.486 283 0.000354 0.839 284 0.000288 0.230 285 0.000107 0.062 286 0.000155 0.050 287 0.000137 0.050 288 0.000484 0.652 289 0.000214 0.131 290 0.000215 0.149 291 0.000083 0.104 292 0.000356 0.399 293 0.000242 0.207 294 0.000660 0.687 295 0.000321 0.104 296 0.000211 1.310 297 0.000128 0.066 298 0.000279 0.262 299 0.000367 0.456 300 0.000165 0.284 301 0.000196 0.141 302 0.000107 0.084 303 0.000150 0.101 304 0.000226 0.239 305 0.000330 0.327 306 0.000282 0.246 307 0.000087 0.041 308 0.000111 0.070 309 0.000215 0.064 310 0.000117 0.517 311 0.000324 0.362 312 0.000576 0.408 313 0.000225 0.131 314 0.000118 0.126 315 0.000122 0.124 316 0.000166 0.047 317 0.000186 0.088 318 0.000138 0.077 319 0.000081 0.087 320 0.000524 0.302 321 0.000145 0.092 322 0.000145 0.087 323 0.000166 0.169 324 0.000136 0.057 325 0.000180 0.192 326 0.000307 0.488 327 0.000214 0.174 328 0.000087 0.048 329 0.000137 0.243 330 0.000425 0.278 331 0.000184 0.230 332 0.000096 0.089 333 0.000088 0.082 334 0.000186 0.159 335 0.000148 0.133 336 0.000085 0.051 337 0.000090 0.059 338 0.000100 0.057 339 0.000117 0.153 340 0.000128 0.060 341 0.000052 0.042 342 0.000089 0.104 343 0.000093 0.094 344 0.000116 0.057 345 0.000803 1.040 346 0.000062 0.066 347 0.000392 0.871 348 0.002625 5.360 349 0.001610 7.790 350 0.012333 >33.3 351 0.000121 0.196 352 0.000111 0.162 353 0.000135 0.186 354 0.000214 0.450 355 0.000172 0.272 356 0.000110 0.367 357 0.000067 0.118 358 0.000066 0.144 359 0.002080 >33.3 360 0.001067 2.410 361 0.000101 0.028 362 0.000061 0.058 363 0.000080 0.101 364 0.192500 >33.3 365 0.000104 0.032 366 0.000248 0.133 367 0.000201 0.273 368 0.000069 0.068 369 — 0.071 370 — 0.369 371 0.000101 0.043 372 0.000175 0.085 373 0.000069 0.060 374 0.000095 0.041 375 0.000102 0.042 376 0.000152 0.064 377 0.000130 0.055 378 0.001187 1.415 379 0.000220 0.235 380 0.000712 0.338 381 0.000157 0.262 382 0.000130 0.106 383 0.000194 0.182 384 0.000324 0.266 385 0.000762 0.717 386 0.000273 0.211 387 0.000291 0.272 388 0.000069 0.194 389 0.000218 0.278 390 0.000095 0.068 391 0.001120 1.710 392 0.000443 4.610 393 0.000079 1.590 394 0.000533 0.461 395 0.000302 1.960 396 0.000084 1.020 397 0.000532 1.820 398 0.001007 5.585 399 0.000401 2.100 400 0.001100 2.872 401 0.002380 2.170 402 0.001399 0.745 403 0.000472 0.215 404 0.000565 0.319 405 0.000057 0.018 406 0.000304 0.329 407 0.000751 0.567 408 0.000225 4.610 409 0.000214 0.140 410 0.000327 0.247 411 0.000930 0.796 412 0.001410 0.749 413 0.000257 0.145 414 0.000154 1.840 415 0.000294 4.020 416 0.000423 6.910 417 0.001750 6.320 418 0.000662 0.515 419 0.003310 2.140 420 0.000176 0.080 421 0.001175 0.596 422 0.000289 0.405 423 0.000269 0.626 424 — 2.240 425 0.000281 0.086 426 0.001315 2.170 427 0.000208 0.141 428 0.000154 0.316 429 0.000214 0.174 430 0.002475 1.310 431 0.000555 0.206 432 0.000229 0.302 433 0.001186 1.670 434 0.000585 0.913 435 0.000380 0.152 436 0.000156 3.200 437 0.000201 0.080 438 0.000308 0.230 439 0.000427 0.505 440 0.000140 0.038 441 0.000459 0.443 442 0.000221 0.286 443 0.001255 0.555 444 0.000128 0.251 445 0.000282 0.161 446 0.000776 0.446 447 0.000119 0.069 448 0.000315 0.581 449 0.000449 0.290 450 0.000112 0.791 451 0.001006 1.810 452 0.003375 17.200 453 0.000451 0.611 454 0.000174 0.213 455 0.000104 0.110 456 0.001045 0.908 457 0.001468 2.610 458 0.000848 0.439 459 0.000225 0.267 460 0.000147 0.161 461 0.000111 0.218 462 0.000261 0.198 463 0.000439 0.322 464 0.000387 0.426 465 0.000581 0.536 466 0.000900 0.446 467 0.000223 0.173 468 0.001075 1.210 469 0.000075 0.295 470 0.000156 0.122 471 0.000321 0.943 472 0.000167 0.068 473 0.000112 0.025 474 0.000088 0.042 475 0.000411 0.350 476 0.000223 0.173 477 0.000240 0.403 478 0.000423 0.197 479 0.000315 4.980 480 0.000067 0.113 481 0.000212 1.110 482 0.000180 0.590 483 0.000244 0.260 484 0.000075 0.162 485 0.000292 1.210 486 0.000081 0.269 487 0.000221 1.500 488 0.000076 0.183 489 0.000035 0.046 490 0.000288 1.860 491 0.000096 0.453 492 0.000295 0.516 493 0.000109 0.170 494 0.000276 1.480 495 0.000075 0.082 496 0.000105 0.207 497 0.000469 1.210 498 0.000120 0.143 499 0.000355 0.110 500 0.000147 0.078 501 0.000672 5.030 502 0.000069 0.191 503 0.000331 0.200 504 0.000159 0.087 506 0.003800 7.430 507 0.013700 >33.3 508 0.000248 1.130 509 0.000155 0.744 510 0.000258 1.520 511 0.000493 1.380 512 0.000170 0.363 513 0.000235 0.383 514 0.000279 0.567 515 0.000113 0.120 516 0.000254 0.209 517 0.000259 0.252 518 0.000164 0.224 519 0.000157 0.116 520 0.000128 0.095 521 0.000133 0.174 522 0.000142 0.110 523 0.000158 0.260 524 — 0.135 525 0.000142 0.087 526 0.000144 0.289 527 0.000804 2.190 528 0.000162 0.140 529 0.005565 2.840 530 0.001200 0.530 531 0.000141 0.138

TABLE 5 Mcl-1 HTRF IC₅₀ OPM-2 10% FBS IC₅₀ IP Example Number (μM) (μM) 100001 0.000055 0.124 100002 0.000071 0.041 100003 0.00042 0.238 100004 0.000072 0.120 100005 0.000091 0.062 100006 0.000081 0.131 100007 0.000367 0.142 100008 0.000170 0.541 100009 0.000128 0.216 100010 0.000077 0.142 100011 0.000153 0.134 100012 0.000275 1.131 100013 0.000199 0.068 100014 0.000228 0.330 100015 0.001040 1.003 100016 0.000182 0.132 100017 0.000039 0.040 100018 0.000061 0.049 100019 0.000182 0.058 100020 0.000032 0.085 100021 0.001053 — 100022 0.000861 — 100023 0.003940 — 100024 0.006155 — 100025 0.002348 — 100026 0.002145 — 100027 0.007340 — 100028 0.001257 — 100029 0.008733 — 100030 0.010355 — 100031 0.007450 — 100032 0.000442 — 100033 0.002815 — 100034 0.000877 — 100035 0.000601 1.470 100036 0.000889 1.980 100037 0.001805 1.920 100038 0.001655 2.560 100039 0.000563 0.744 100040 0.002745 4.950 100041 0.003365 4.990 100042 0.004860 2.220 100043 0.001670 7.280 100044 0.031100 7.290 100045 0.000308 0.342 100046 0.003760 0.976 100047 0.005150 2.540 100048 0.000187 0.551 100049 0.001261 2.150 100050 0.001282 3.824 100051 0.000217 0.502 100052 0.000191 0.424 100053 0.000294 0.609 100054 0.004110 9.060 100055 0.001270 4.630 100056 0.000424 1.680 100057 0.000568 2.600 100058 0.001760 3.360 100059 0.011900 3.450 100060 0.004010 5.980 100061 0.000780 0.529 100062 0.004250 9.940 100063 0.002320 2.260 100064 0.002540 3.730 100065 0.004855 7.390 100066 0.001430 3.820 100067 0.001009 0.271 100068 0.004410 0.765 100069 0.000457 0.250 100070 0.004855 1.070 100071 0.001540 0.588 100072 0.000451 1.720 100073 0.000346 1.197 100074 0.000731 3.020 100075 0.000671 1.817 100076 0.009655 2.670 100077 0.000190 0.052 100078 0.000409 2.720 100079 0.000343 0.713 100080 0.000610 0.818 100081 0.007330 5.930 100082 0.000539 0.727 100083 0.000179 0.123 100084 0.000745 1.488 100085 0.000245 0.288 100086 0.000537 0.390 100087 0.000864 0.187 100088 0.002125 1.340 100089 0.000348 0.325 100090 0.000795 0.798 100091 0.001195 1.350 100092 0.004015 2.210 100093 0.000291 0.554 100094 0.003835 4.380 100095 0.000148 0.113 100096 0.000624 0.517 100097 0.000081 5.230 100098 0.000231 0.748 100099 0.000659 0.349 100100 0.002100 1.325 100101 0.000062 2.595 100102 0.000990 1.430 100103 0.000325 0.778 100104 0.000599 0.250 100105 0.005930 3.660 100106 0.000143 0.121 100107 0.000296 0.181 100108 0.000436 0.358 100109 0.000486 2.140 100110 0.001480 0.686 100111 0.000352 0.687 100112 0.001295 1.800 100113 0.000182 0.070 100114 0.001052 0.491 100115 0.004485 2.840 100116 0.003775 5.940 100117 0.002405 3.170 100118 0.004440 3.950 100119 0.001720 1.570 100120 0.000067 0.635 100121 0.000056 2.530 100122 0.000098 1.190 100123 0.000092 2.660 100124 0.000323 0.270 100125 0.000430 0.555 100126 0.000183 0.041 100127 0.000175 0.108 100128 0.000089 0.217 100129 0.002400 4.870 100130 0.002690 2.170 100131 0.000163 0.144 100132 0.000543 0.675 100133 0.000885 0.984 100134 0.000845 3.510 100135 0.000173 0.161 100136 0.000368 0.556 100137 0.000365 2.820 100138 0.000549 0.342 100139 0.002585 0.974 100140 0.000486 0.299 100141 0.001058 1.370 100142 0.000717 0.663 100143 0.001870 3.270 100144 — 0.208 100145 0.000357 0.945 100146 0.000515 0.347 100147 0.000305 0.666 100148 0.000113 0.239 100149 0.000214 0.186 100150 0.001685 1.430 100151 0.000120 0.071 100152 0.000449 0.377 100153 0.000738 4.660 100154 0.001720 1.070 100155 0.000225 0.332 100156 0.000410 0.568 100157 0.004810 3.210 100158 0.000298 0.260 100159 0.000559 0.591 100160 0.000169 0.078 100161 0.000355 0.757 100162 0.003470 2.870 100163 0.002790 1.000 100164 0.000917 0.967 100165 0.000455 0.579 100166 0.001765 0.945 100167 0.000377 0.339 100168 0.000249 0.196 100169 0.004825 2.270 100170 0.012100 7.820 100171 0.000578 0.868 100172 0.001295 1.570 100173 0.000539 0.379 100174 0.002025 1.910 100175 0.000149 0.452 100176 0.000480 0.603 100177 0.000258 0.259 100178 0.000432 0.237 100179 0.005810 0.840 100180 0.004917 4.425 100181 0.000537 0.226 100182 0.000863 0.827 100183 0.001340 2.245 100184 0.000717 0.179 100185 0.008883 5.130 100186 0.000377 0.312 100187 0.002760 3.110 100188 0.000877 0.735 100189 0.000820 0.701 100190 0.004790 2.480 100191 0.001600 0.557 100192 0.000192 0.149 100193 0.000856 1.300 100194 0.000613 0.619 100195 0.001075 0.625 100196 0.000461 0.358 100197 0.000774 2.460 100198 0.000307 0.399 100199 0.000166 0.148 100200 0.000213 1.070 100201 0.000086 0.307 100202 0.000352 0.928 100203 0.000285 0.491 100204 0.001655 5.270 100205 0.000206 0.068 100206 0.001260 1.750 100207 0.000141 0.215 100208 0.000431 0.318 100209 0.002675 3.380 100210 0.003475 3.360 100211 0.001435 4.780 100212 0.000901 1.620 100213 0.002845 2.020 100214 0.000143 0.095 100215 0.000595 1.250 100216 0.000311 0.374 100217 0.000183 0.130 100218 0.000621 0.675 100219 0.000401 0.974 100220 0.007415 6.840 100221 0.000525 0.776 100222 0.000182 0.222 100223 0.001410 2.150 100224 0.000345 0.385 100225 0.000639 0.882 100226 0.001395 0.849 100227 0.000423 0.191 100228 0.000558 3.300 100229 0.000356 1.490 100230 0.000473 0.544 100231 0.000312 0.350 100232 0.000152 0.389 100233 0.001040 0.257 100234 0.000237 0.449 100235 0.001345 0.644 100236 0.001096 0.933 100237 0.001740 0.996 100238 0.000474 0.747 100239 0.000333 3.740 100240 0.000385 0.266 100241 0.000365 0.401 100242 0.002145 1.450 100243 0.011500 8.670 100244 0.000182 0.049 100245 0.001715 1.980 100246 0.000326 0.114 100247 0.000542 0.624 100248 0.011050 6.680 100249 0.002995 2.270 100250 0.000136 0.082 100251 0.003290 3.730 100252 0.000112 0.077 100253 0.000149 0.544 100254 0.004070 2.150 100255 0.014450 5.020 100256 0.005040 1.200 100257 0.000180 0.080 100258 0.000553 0.519 100259 0.006180 1.250 100260 0.000408 0.094 100261 0.001220 0.533 100262 0.000134 0.433 100263 0.001830 3.390 100264 0.000384 0.600 100265 0.000439 0.441 100266 0.000292 0.571 100267 0.000166 0.274 100268 0.003440 3.810 100269 0.000908 1.230 100270 0.000776 3.72 100271 0.002480 6.120 100272 0.000401 0.349 100273 0.005655 8.660 100274 0.000377 0.543 100275 0.000113 0.309 100276 0.000326 1.528 100277 0.000266 0.448 100278 0.000458 0.333 100279 0.000777 3.25 100280 0.000368 0.305 100281 0.000117 0.352 100282 0.000268 1.280 100283 0.000143 0.806 100284 0.000285 0.396 100285 0.000241 0.642 100286 0.000471 1.580 100287 0.000494 1.870 100288 0.000103 0.089 100289 0.000878 3.960 100290 0.000116 0.259 100291 0.000137 0.281 100292 0.000115 0.672 100293 0.000522 0.726 100294 0.000118 0.116 100295 0.000279 0.302 100297 0.000115 0.168 100298 0.000140 0.199 100299 0.000350 0.623 100300 0.000109 0.235 100301 0.001315 1.930 100302 0.003805 4.880 100303 0.003640 7.330 100304 0.000311 0.464 100305 0.000473 1.140 100306 0.000124 0.278 100307 0.000049 1.030 100308 0.000033 1.170 100309 0.000244 0.385 100310 0.000152 0.120 100311 0.001030 1.190 100312 0.000088 0.234 100313 0.000129 0.143 100314 0.002925 2.290 100315 0.000200 0.153 100316 0.000276 0.375 100317 0.000188 0.157 100318 0.000095 0.114 100319 0.000126 0.506 100320 0.001200 2.140 100321 0.000209 0.285 100322 0.00223 1.54 100323 0.000477 1.250 100324 0.000244 1.170 100325 0.000182 0.482 100326 0.000615 0.334 100327 0.000295 0.550 100328 0.000261 0.180 100329 0.005023 1.560 100330 0.000083 8.260 100331 0.000192 8.260 100332 0.006465 4.31 100333 0.002100 2.170 100334 0.003273 1.470 100335 0.000319 0.165 100336 0.001123 1.810 100337 0.001608 2.410 100338 0.000502 1.920 100339 0.000186 1.380 100340 0.000779 0.308 100341 0.0041 1.94 100342 0.001685 0.782 100343 0.002510 0.617 100344 0.000309 0.290 100345 0.002420 0.218 100346 0.000735 0.248 100347 0.000689 1.080 100348 0.000135 0.125 100349 0.00115 0.058 100350 0.000489 0.554 100351 0.000115 2.02 100352 0.002750 0.246 100353 0.000348 0.151 100354 0.000109 0.147 100355 0.000535 0.776 100356 0.000084 0.071 100357 0.000224 0.399 100358 0.000118 0.081 100359 0.001200 1.540 100360 0.000848 1.230 100361 0.000208 0.155 100362 0.000888 2.1 100363 0.001383 3.810 100364 0.001160 1.680 100365 0.000257 0.245 100366 0.000198 0.168 100367 0.000371 0.604 100368 0.000377 0.611 100369 0.00283 9.92 100370 0.000153 0.258 100371 0.00039 0.307 100372 0.000165 0.833 100373 0.000318 0.736 100374 0.000289 0.433 100375 0.000070 0.176 100376 0.000150 0.362 100377 0.000107 0.182 100378 0.000037 0.111 100379 0.000060 0.071 100380 0.000208 0.137 100381 0.000328 2.910 100382 0.000471 0.312 100383 0.000264 3.430 100384 0.000821 0.729 100385 0.000144 0.144 100386 0.004017 7.27 100387 0.000175 3.760 100388 0.001167 2.160 100389 0.000101 0.114 100390 0.000186 0.649 100391 0.000441 0.282 100392 0.000112 0.129 100393 0.000164 0.211 100394 0.000242 0.622 100395 0.000056 0.040 100396 0.000272 1.470 100397 0.000198 0.404 100398 0.000618 0.457 100399 0.000280 2.810 100400 0.000838 1.320 100401 0.001797 8.390 100402 0.000098 0.133 100403 0.000226 0.39 100404 0.002553 8.15 100405 0.000545 1.120 100406 0.000360 0.747 100407 0.000278 0.516 100408 0.001353 5.62 100409 0.000124 0.206 100410 0.000127 0.297 100411 0.000584 2.1 100412 0.000097 0.249 100413 0.000228 0.556 100414 0.000626 1.270 100415 0.001950 2.285 100416 0.000092 0.086 100417 0.000345 0.379 100418 0.000098 0.141 100419 0.000277 0.416 100420 0.000112 0.161 100421 0.003926 4.93 100422 0.000174 0.182 100423 0.000056 0.099 100424 0.000249 0.469 100425 0.000165 0.717 100426 0.000197 0.110 100427 0.000209 0.342 100428 0.000210 0.218 100429 0.000176 1.420 100430 0.000057 0.358 100431 0.000043 0.290 100432 0.000228 0.711 100433 0.000026 0.296 100434 0.000162 0.482 100435 0.000055 0.305 100436 0.000076 0.335 100437 0.000073 0.531 100438 0.000169 0.547 100439 0.000619 2.640 100440 0.000398 0.354 100441 0.000133 0.154 100442 0.000921 3.870 100443 0.000070 0.156 100444 0.000098 0.646 100445 0.000040 0.098 100446 0.000126 0.345 100447 0.000050 0.184 100448 0.000373 1.920 100449 0.000071 0.171 100450 0.000336 1.910 100451 0.000111 0.412 100452 0.000077 0.157 100453 0.000927 2.930 100454 0.000652 0.802 100455 0.000087 0.140 100456 0.000565 1.230 100457 0.000331 0.967 100458 0.000210 0.418 100459 0.000685 0.732 100460 0.000095 0.433 100461 0.000042 0.382 100462 0.000304 0.652 100463 0.000383 1.130 100464 — 1.530 100465 0.000121 0.729 100466 0.000043 1.440 100467 0.000303 0.516 100468 0.000393 0.943 100469 0.000085 0.325 100470 0.000576 9.65 100471 0.000281 0.299 100472 0.000651 0.357 100473 0.000974 0.178 100474 0.000405 0.387 100475 0.001365 2.710 100476 — 1.340 100477 0.000313 0.159 100478 0.003470 4.090 100479 0.000758 0.332 100480 0.000176 0.221 100481 0.000094 0.152 100482 0.000183 0.105 100483 0.001664 1.690 100484 0.003850 3.370 100485 0.000192 0.272 100486 0.000381 0.102 100487 0.000436 0.340 100488 0.000389 0.346 100489 0.000880 0.182 100490 0.000292 0.511 100491 0.000208 0.308 100492 0.000749 0.436 100493 0.000322 0.512 100494 0.000078 0.089 100495 0.000462 0.539 100496 0.002665 5.060 100497 0.000064 0.106 100498 0.000885 1.660 100499 0.000509 1.120 100500 0.000049 0.071 100501 0.000090 0.518 100502 0.000290 0.393 100503 0.000493 0.706 100504 0.000803 1.890 100505 0.000165 0.137 100506 0.000497 1.270 100507 0.000430 0.490 100508 0.002734 2.500 100509 0.000057 0.361 100510 0.000070 0.379 100511 0.000070 0.430 100512 0.000415 1.490 100513 0.000071 0.288 100514 0.000088 0.231 100515 0.000132 0.585 100516 0.003360 1.900 100517 0.001059 3.460 100518 0.000427 0.668 100519 0.000175 0.138 100520 0.000549 1.690 100521 0.000197 0.296 100522 0.000144 0.538 100523 0.000812 0.622 100524 0.000990 0.842 100525 0.003305 1.430 100526 0.000387 0.826 100527 0.003595 3.570 100528 0.000138 0.257 100529 0.000287 0.245 100530 0.000171 0.448 100531 0.000083 0.172 100532 0.000053 8.637 100533 0.008565 3.990 100534 0.000799 0.542 100535 0.000570 0.964 100536 0.000204 0.826 100537 0.000115 0.256 100538 0.001470 2.400 100539 0.000144 0.727 100540 0.000275 0.320 100541 0.000760 0.826 100542 0.000229 0.902 100543 0.000451 0.821 100544 0.000171 0.306 100545 0.000153 0.231 100546 0.000084 0.440 100547 0.000031 1.860 100548 0.000064 8.410 100549 0.002570 0.545 100550 0.000059 6.859 100551 0.000174 0.142 100552 0.000065 0.957 100553 0.001040 2.790 100554 0.000231 0.519 100555 0.000101 0.113 100556 0.000113 0.734 100557 0.000093 0.299 100558 0.000086 0.274 100559 0.000113 1.030 100560 0.000041 2.020 100561 0.000275 0.673 100562 0.000057 0.532 100563 0.000065 0.510 100564 0.000333 1.430 100565 0.001540 2.060 100566 0.000142 0.590 100567 0.000125 0.249 100568 0.000431 1.540 100569 0.002479 2.000 100570 0.003380 5.050 100571 0.000076 0.922 100572 0.000174 1.160 100573 0.002070 7.390 100574 0.001420 4.320 100575 0.001300 2.500 100576 0.001150 4.090 100577 0.000045 2.020 100578 0.000089 0.595 100579 0.000214 0.757 100580 0.000877 6.580 100581 0.000363 1.540 100582 0.000197 1.120 100583 0.000124 0.411 100584 0.000139 0.349 100585 0.000057 0.696 100586 0.000074 0.453 100587 0.000136 0.177 100588 0.000075 0.117 100589 0.001835 3.330 100590 0.000086 0.501 100591 0.000075 0.060 100592 0.000275 0.139 100593 0.000464 0.215 100594 0.000143 0.241 100595 0.000157 0.133 100596 0.000229 0.186 100597 0.000263 0.577 100598 0.000077 0.188 100599 0.001150 1.140 100600 0.000445 0.528 100601 0.000114 0.239 100602 0.000800 2.330 100603 0.000651 1.570 100604 0.000723 4.110 100605 0.003245 7.950 100606 0.000209 0.428

In-Vivo Data Tumor Pharmacodynamics (PD)

FIGS. 1-7 illustrate the PD results of the cited Examples. The Reference Compound 1, an internal Amgen MCl-1 inhibitor compound made by one of the general schemes outlined in U.S. Pat. No. 9,562,061, herein incorporated by reference, is (1S,3′R,6′R,7′S,8′E,12′R)-6-chloro-12′-ethyl-7′-methoxy-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0˜3,6˜.0˜19,24˜]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide

Female Athymic nude (Charles River Laboratories, Inc., Hollister Calif.) mice were inoculated subcutaneously with 5×10⁶ OPM-2 Luc cells. When tumors reached 300-500 mm³ in size, mice were randomized into treatment groups and harvested 6 hours post single dose of compound at various concentrations. Tumor lysates were analyzed for active Bak using a sandwich ELISA format (Active Bak MSD plate cat #N45ZA-1; Bak detection antibody Abcam Cat# Ab53153 and Sulfo-Tagged by MSD) and read on a MSD reader (S16000). Columns (n=3 per group) represent level of luminescence (cps). Statistical significance was determined by Oneway ANOVA followed by Dunnett's post hoc compared to the vehicle control group. Black diamonds represent drug plasma concentration and circles represent drug concentration in the tumor.

OPM-2 Xenograft

Examples 8-13 illustrate Xenograft data of various compounds of the present invention. Female Athymic nude (Charles River Laboratories, Inc., Hollister Calif.) mice were inoculated subcutaneously with 5×10⁶ OPM-2 Luc cells. When average tumor volumes reached approximately 155-183 mm³, animals were randomized (n=10/group) and dosed once daily by oral gavage (10-12 days) with test compounds at various concentrations unless notes otherwise. Tumor volume and body weights were recorded twice per week using electronic calipers and an analytical scale. Statistical analysis was performed using Repeated Measures ANOVA (RMANOVA) followed by Dunnett's post-hoc analysis.

The foregoing description is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds, compositions and methods. Variations and changes, which are obvious to one skilled in the art, are intended to be within the scope and nature of the invention, as defined in the appended Claims. From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. All patents and other publications recited herein are hereby incorporated by reference in their entireties. 

1. A compound of Formula I:

a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, wherein: Z is C or N; Q is O, S, CR^(WA)R^(WB), or NR^(a)R^(b); W is CR^(WA)R^(WB), —C═O, or is absent; R^(WA) and R^(WB) are independently selected from H, —C₁₋₃alkyl, —C₁₋₃alkenyl, —C₁₋₃alkynyl, halo, —OH, or —O—C₁₋₃alkyl; b, represented by the symbol

, is a single or double chemical bond which may be cis or trans; R¹ is independently selected from H, halo, C₁₋₆alkylhalo, C₁₋₆alkyl, C₂₋₆alkenyl, —(CH₂CH₂)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), or —C(═O)NR^(a)R^(b); R² is selected from H, halo, C₁₋₆haloalkyl, C₁₋₆alkyl, O—C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), —C(═O)NR^(a)R^(b), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl or heterocycloalkyl group have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O or SO₂; R³ is selected from H, —C₁₋₆alkylhalo, —C₁₋₆alkyl, —C₂₋₆alkenyl, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a), —C(═O)OR^(a), or —C(═O)NR^(a)R^(b); each of R^(2B), R^(2C), R⁴, R⁵, R⁶, R⁷, and R⁸ is independently selected from H, halo, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), —C(═O)NR^(a)R^(b), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂; alternatively R³ and R⁴ together with the atoms to which they are bonded may form a 5- to 12-membered ring, optionally containing a heteroatom selected from a N, O or S atom, in addition to the S and N atoms present in the ring, wherein the ring may optionally contain at least one double bond; and the ring may be substituted with 0, 1, 2, or 3 R^(3A) substituents; wherein R^(3A) is selected from H, halo, —OH, C₁₋₆haloalkyl, C₁₋₆alkyl, O—C₁₋₆alkyl, C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), or —C(═O)NR^(a)R^(b); each of R^(4A), R^(5A), R^(6A), R^(7A), and R^(8A) is independently selected from H, OH, halo, or —C₁₋₆alkyl; R^(7A) and R^(8A) are absent when b is a double chemical bond; alternatively R⁷ and R⁸ together with the atoms to which they are bonded may form a 3- to 12-membered ring, wherein the ring may optionally contain at least one double bond; R⁹ is independently selected from H, OH, -(═O), —C₁₋₆haloalkyl, —C₁₋₆alkyl, —C₁₋₆alkenylene, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —C₁₋₆alkyl-O—C₁₋₆alkyl, cyano, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl or heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl group may include a C═O group, and further wherein the spiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O or SO₂; R^(9A) is independently selected from H, —OH, halo, cyano, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —(CH₂CH₂O)_(n)R^(a), —P(═O)OR^(a)OR^(b), —CSR^(a), —CS(═O)R^(a), —SR^(a), —SOR^(a), —OSO₂R^(a), —SO₂R^(a), —(CH₂CH₂O)_(n)CH₃, -(═O), —C(═O), —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —CH₂—NR^(a)R^(b), —NR^(a)R^(b), —C₁₋₆alkyl-O—C₁₋₆alkyl, —OC₁₋₆alkyl, —O—C₁₋₆alkyl-O—C₁₋₆alkyl, phenyl, a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may contain a double bond and may contain a C═O group, and further wherein the spiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O or SO₂; wherein R^(9A) is not H when W is absent; wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of the R^(9A) substituent can be unsubstituted or substituted with 1, 2, 3 or 4 R¹⁰ substituents independently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆alkynyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 0, 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂; alternatively R⁷ and R^(9A) together with the atoms to which they are bonded may form a 3- to 12-membered ring, wherein the ring may optionally contain at least one double bond; alternatively R⁹ and R^(9A) together with Q, W, and the C to which W and Q are bonded, may form a 3- to 12-membered monocyclic or bicyclic ring, optionally containing a heteroatom in addition to Q that is selected from N, O or S, wherein the ring may contain a double bond, wherein the ring may optionally include a C═O group, and further wherein the ring optionally may be substituted by 1, 2, or 3 R¹¹ substituents; R¹¹ is independently selected from H, —OH, halo, —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —NR^(c)R^(d), —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(c), —C(═O)OR^(c), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl group may include a double bond, and wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl group may include a C═O group, and further wherein the spiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O or SO₂; wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and the —OC₁₋₆alkyl of any of the R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R^(4A), R^(5A), R^(6A), R^(7A), R^(8A), R^(9A), R^(WA) and R^(WB) substituents is unsubstituted or substituted by 1, 2 or 3 R¹² substituents independently selected from OH, —OC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, halo, —O-haloC₁₋₆alkyl, —CN, —NR^(a)R^(b), —(NR^(a)R^(b)R^(c))_(n), —OSO₂R^(a), —SO₂R^(a), —(CH₂CH₂O)_(n)CH₃, -(═O), —C(═O), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —O—SiR^(a)R^(b)R^(c), —SiR^(a)R^(b)R^(c), —O-(3- to 10-membered heterocycloakyl), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O or SO₂; wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl group of any of the R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9A), R¹⁰, R¹¹, R¹², R^(WA) and R^(WB) substituents can be unsubstituted or substituted with 1, 2, 3 or 4 R¹³ substituents independently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups of R¹³ have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, and spiroheterocycloalkyl groups of R¹³ or the heterocycloalkyl group of R¹³ may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂; wherein each R^(a), R^(b), R^(c), and R^(d) is independently hydrogen, OH, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₁₋₆alkyl-NR¹⁴R¹⁴, —NR¹⁴R¹⁴, —SO₂R¹⁴-(CH₂CH₂O)_(n)CH₃, -(═O), —C(═O)R¹⁴, —OC(═O)R¹⁴, —C(═O)OR¹⁴, —C(═O)NR¹⁴R¹⁴, —C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, benzyl, phenyl, —C₁₋₆alkyl-C(═O)OH, —C₁₋₆alkyl-C(═O)—O—C₁₋₆alkyl, —C₁₋₆alkyl-cycloalkyl, —C₁₋₆alkyl-heterocycloalkyl, —C₁₋₆alkyl-6- to 12-membered aryl, —C₁₋₆alkyl-6- to 12-membered heteroaryl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, where the heteroaryl, spiroheterocycloalkyl, heterocycloalkyl group or the —C₁₋₆alkyl-heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, heterocycloalkyl, group of R^(a), R^(b), R^(c), and R^(d) or the heterocycloalkyl group or the —C₁₋₆alkyl-heterocycloalkyl group may include a double bond and may contain a C═O group, and the spiroheterocycloalkyl, or heterocycloalkyl may include a S═O or SO₂; the alkyl, aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, or heterocycloalkyl group of R^(a), R^(b), R^(c), and R^(d) and the heterocycloalkyl group of the —C₁₋₆alkyl-heterocycloalkyl group of R^(a), R^(b), R^(c), and R^(d) can be unsubstituted or substituted with 1, 2, 3, or 4 R¹⁴ substituents, wherein each R¹⁴ is independently selected from H, —OH, —N═N═N, halo, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, phenyl, tolyl, —C(═O)C₁₋₆alkyl, —C(═O)O—C₁₋₆alkyl, N(CH₃)₂ or —SO₂—N(CH₃)₂; and wherein n is independently in each instance an integer of 1, 2, 3 or
 4. 2. The compound of claim 1, wherein the compound has the Formula II:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof.
 3. The compound of claim 1, wherein the compound has the Formula IIa:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof.
 4. The compound of claim 1, wherein the compound has a structure selected from:

or the stereoisomer thereof; the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof.
 5. A compound of Formula I′:

or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, wherein: Z is C or N; Q is O or S; W is CR^(WA)R^(WB) or C═O; R^(WA) and R^(WB) are independently selected from H, C₁₋₃alkyl, halo, —OH, or —O—C₁₋₃alkyl; b, represented by the symbol

is a single or double chemical bond which may be cis or trans; R¹ is independently selected from H, halo, C₁₋₆alkylhalo, C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), or —C(═O)NR^(a)R^(b); R² is selected from H, halo, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), or —C(═O)NR^(a)R^(b), R³ is independently selected from H, —C₁₋₆alkylhalo, —C₁₋₆alkyl, —C₂₋₆ alkenyl, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a), —C(═O)OR^(a), or —C(═O)NR^(a)R^(b); each of R⁴, R⁵, R⁶, R⁷, and R⁸ is independently selected from H, halo, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), —C(═O)NR^(a)R^(b), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂; alternatively R³ and R⁴ together with the atoms to which they are bonded may form a 5- to 12-membered ring, optionally containing a heteroatom selected from a N, O or S atom, in addition to the S and N atoms present in the ring, wherein the ring may optionally contain at least one double bond; and the ring may be substituted with 0, 1, 2, or 3 R^(3A) substituents; R^(3A) is independently selected from H, halo, —OH, C₁₋₆haloalkyl, C₁₋₆alkyl, O—C₁₋₆alkyl, C₂₋₆alkenyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), —C(═O)NR^(a)R^(b); each of R^(4A), R^(5A), R^(6A), R^(7A), and R^(8A) is independently selected from H, OH, halo, or —C₁₋₆alkyl; R^(7A) and R^(8A) are absent when b is a double chemical bond; R⁹ is independently selected from H, —C₁₋₆haloalkyl, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —(CH₂CH₂O)_(n)R^(a), —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂; R^(9A) is independently selected from H, C₁₋₆haloalkyl, C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b), —N═N═N, —C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂; wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of the R^(9A) substituent can be unsubstituted or substituted with 1, 2, 3 or 4 R¹⁰ substituents independently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆alkynyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 0, 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂; alternatively R⁹ and R^(9A) together with Q, W, and the C to which W and Q are bonded, may form a 3- to 12-membered monocyclic or bicyclic ring, optionally containing a heteroatom in addition to Q that is selected from N, O or S, wherein the ring may contain a double bond, wherein the ring may optionally include a C═O group, and further wherein the ring optionally may be substituted by 1, 2, or 3 R¹¹ substituents; R¹¹ is independently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl group have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂; wherein the —C₁₋₆alkyl of any of the R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R^(4A), R^(5A), R^(6A), R^(7A), R^(8A), and R^(9A) substituents is unsubstituted or substituted by 1, 2 or 3 R¹² substituents independently selected from OH, —OC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, halo, —O-haloC₁₋₆alkyl, —CN, —NR^(a)R^(b), —(NR^(a)R^(b)R^(c))_(n), —SO₂R^(a), —(CH₂CH₂O)_(n)CH₃, (═O), —C(═O), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —O—SiR^(a)R^(b)R^(c), —O-(3- to 12-membered heterocycloakyl), phenyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂; wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of any of the R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² substituents can be unsubstituted or substituted with 1, 2, 3 or 4 R¹³ substituents independently selected from OH, halo, —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —NR^(c)R^(d), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), —B(OH)₂, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂; wherein each R^(a), R^(b), R^(c), and R^(d) is independently H, OH, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₂₋₆alkynyl, —C₁₋₆alkyl-NR¹⁴R¹⁴, NR¹⁴R¹⁴, —SO₂R¹⁴, —(CH₂CH₂O)_(n)CH₃, (═O), —C(═O)R¹⁴, —OC(═O)R¹⁴, —C(═O)OR¹⁴, —C(═O)NR¹⁴R¹⁴, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, —C₁₋₆alkyl-OH, benzyl, phenyl, a —C₁₋₆alkyl-3- to 12-membered heterocycloalkyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups and r the heterocycloalkyl group of the —C₁₋₆alkyl-heterocycloalkyl group have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, heterocycloalkyl, and the heterocycloalkyl groups of the —C₁₋₆alkyl-heterocycloalkyl group may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂; the alkyl, aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, heterocycloalkyl and the heterocycloalkyl groups of the —C₁₋₆alkyl-heterocycloalkyl groups of R^(a), R^(b), R^(c), and R^(d) can be unsubstituted or substituted with 1, 2, 3, or 4 R¹⁴ substituents independently selected from H, OH, —N═N═N, halo, —C₁₋₆alkyl, —OC₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, phenyl, tolyl, —C(O)C₁₋₆alkyl, —C(O)OCH₃, SO₂-phenyl, or —SO₂—N(CH₃)₂; and n is independently, in each instance, an integer of 1, 2, 3 or
 4. 6. The compound of claim 5, wherein the compound of Formula I′ has the Formula I′a:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof.
 7. The compound of claim 5, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein b is a double bond.
 8. The compound of claim 5, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein Z is C.
 9. The compound of claim 5, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein Z is N.
 10. The compound of claim 5, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein Q is O.
 11. The compound of claim 5, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein W is CR^(WA)R^(WB).
 12. The compound of claim 11, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(WA) and R^(WB) are both H.
 13. The compound of claim 5, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹ is halo.
 14. The compound of claim 13, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹ is Cl.
 15. The compound of claim 5, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R² is H.
 16. The compound of claim 5, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R³ is H or —C₁₋₆ alkyl.
 17. The compound of claim 16, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R³ is —CH₃.
 18. The compound of claim 16, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R³ is H.
 19. The compound of claim 5, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ selected from H, —C₁₋₆alkyl, —C₁₋₆alkylhalo, —C₁₋₆alkyl-O—C₁₋₆alkyl, or —(CH₂CH₂O)_(n)R^(a), wherein the —C₁₋₆alkyl is unsubstituted or substituted with —OH, (═O), phenyl, —O—SiR^(a)R^(b)R^(c), —NR^(a)R^(b), a 3- to 12-membered cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from O, N or S.
 20. The compound of claim 19, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is H.
 21. The compound of claim 19, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —C₁₋₆alkyl.
 22. The compound of claim 5, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —CH₃.
 23. The compound of claim 5, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —CH₂CH₂OCH₃.
 24. The compound of claim 5, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵ is H or —C₁₋₆ alkyl.
 25. The compound of claim 24, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵ is —CH₃.
 26. The compound of claim 5, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶ is H or —C₁₋₆ alkyl.
 27. The compound of claim 26, wherein or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, R⁶ is H.
 28. The compound of claim 5, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein each of R^(4A), R^(5A), R^(6A), R^(7A) and R^(8A) is independently selected from H, OH, halo, or —C₁₋₆alkyl.
 29. The compound of claim 28, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein each of R^(4A), R^(5A), R^(6A), R^(7A) and R^(8A) is H.
 30. The compound of claim 5, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is independently selected from H, —C₁₋₆alkyl, —C₂₋₆alkenyl, or —C₁₋₆alkyl-O—C₁₋₆alkyl or —C₁₋₆haloalkyl.
 31. The compound of claim 30, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is H.
 32. The compound of claim 30, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is —CH₃.
 33. The compound of claim 30, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is —CH₂CH₃.
 34. The compound of claim 5, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^(9A) is selected from H, C₁₋₆haloalkyl, C₁₋₆alkyl, —C₂₋₆alkenyl-(CH₂CH₂O)_(n)R^(a), —SO₂R^(a), —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b), —N═N═N, —C₁₋₆alkyl-O—C₁₋₆alkyl, a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂.
 35. The compound of claim 34, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein the 3- to 12-membered monocyclic heterocycloalkyl R^(9A) group can be unsubstituted or substituted with 1, 2, 3 or 4 R¹⁰ substituents independently selected from OH, halo, —NR^(c)R^(d), —C₁₋₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆alkynyl, —OC₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, —O-haloC₁₋₆alkyl, —SO₂R^(c), —CN, —C(═O)NR^(c)R^(d), —C(═O)R^(c), —OC(═O)R^(a), —C(═O)OR^(c), a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, or heterocycloalkyl group have from 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO₂.
 36. The compound of claim 35, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein the 1, 2, 3 or 4 R¹⁰ substituents are independently selected from —C₁₋₆alkyl or a 3- to 12-membered monocyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.
 37. The compound of claim 34, wherein R^(9A) is independently selected from —N═N═N,

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof.
 38. The compound of claim 5, wherein the compound of Formula I′ has Formula II′:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴, R⁵, R⁹ and R^(9A) are as defined above.
 39. The compound of claim 5, wherein the compound of Formula I′ has Formula II′a:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴, R⁵, R⁹ and R^(9A) are as defined above.
 40. The compound of claim 5, wherein the compound of Formula I′ has Formula IV′:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof wherein R⁴, R⁵, R⁹ and R^(9A) are as defined above.
 41. The compound of claim 5, wherein the compound of Formula I′ has Formula IV′a:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴, R⁵, R⁹ and R^(9A) are as defined above.
 42. A compound having a structure selected from:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof.
 43. The compound of claim 42 or the pharmaceutically acceptable salt thereof.
 44. The compound of claim 5, wherein the compound is selected from:

or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof.
 45. The compound of claim 44 or the pharmaceutically acceptable salt thereof.
 46. A pharmaceutical composition comprising the compound of claim 1 or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
 47. A pharmaceutical composition comprising the compound of claim 5 or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
 48. A pharmaceutical composition comprising the compound of claim 42 or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
 49. A pharmaceutical composition comprising the compound of claim 44 or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
 50. A method of treating cancer, the method comprising: administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 or the pharmaceutically acceptable salt thereof.
 51. The method of claim 50, wherein the cancer is a hematologic malignancy.
 52. The method of claim 50, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia, and acute myelogenous leukemia.
 53. The method of claim 50, wherein the cancer is multiple myeloma.
 54. The method of claim 50, wherein the cancer is acute myelogenous leukemia.
 55. The method of claim 50, wherein the cancer is non-Hodgkin's lymphoma.
 56. The method of claim 50, further comprising administering to the patient in need thereof a therapeutically effective amount of an additional pharmaceutically active compound.
 57. The method of claim 56, wherein the additional pharmaceutically active compound is carfilzomib.
 58. The method of claim 56, wherein the additional pharmaceutically active compound is venetoclax.
 59. The method of claim 56, wherein the additional pharmaceutically active compound is cytarabine.
 60. A method of treating cancer, the method comprising: administering to a patient in need thereof a therapeutically effective amount of the compound of claim 44 or the pharmaceutically acceptable salt thereof.
 61. The method of claim 60, wherein the cancer is a hematologic malignancy.
 62. The method of claim 60, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia, and acute myelogenous leukemia.
 63. The method of claim 60, wherein the cancer is multiple myeloma.
 64. The method of claim 60, wherein the cancer is acute myelogenous leukemia.
 65. The method of claim 60, wherein the cancer is non-Hodgkin's lymphoma.
 66. The method of claim 60, further comprising administering to the patient in need thereof a therapeutically effective amount of an additional pharmaceutically active compound.
 67. The method of claim 66, wherein the additional pharmaceutically active compound is carfilzomib.
 88. The method of claim 66, wherein the additional pharmaceutically active compound is venetoclax.
 69. The method of claim 66, wherein the additional pharmaceutically active compound is cytarabine. 